Publications by authors named "Jennifer Diamond"

58 Publications

A Phase 1 Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel using a novel Randomized Continual Reassessment Method for Dose Escalation.

Clin Cancer Res 2021 Sep 13. Epub 2021 Sep 13.

Department of Medical Oncology, Erasmus MC Cancer Institute

Purpose: MPS1 kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase 1 study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination.

Experimental Design: Patients with solid tumors were randomized to receive oral BAY (BID 2‑days‑on/5‑days‑off) with weekly paclitaxel (90 mg/m) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the maximum tolerated dose (MTD) of BAY and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination.

Results: In total, 75 patients were enrolled. The main dose limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg BID with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade {greater than or equal to}3 neutropenia to higher BAY exposure (AUC (< .001)). After determining the MTD, we included nineteen breast cancer patients at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%) and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD.

Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure-toxicity relation for BAY. Therefore we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4185DOI Listing
September 2021

Moving Towards Targeted Therapies for Triple-Negative Breast Cancer.

Curr Breast Cancer Rep 2021 Sep 4;13(3):216-226. Epub 2021 May 4.

Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, United States of America.

Purpose Of Review: In this review, we discuss targets of interest in Triple-negative breast cancer (TNBC), approved targeted agents and the results of the clinical trials that led to their approval. Additionally, we review ongoing clinical trials evaluating the use of novel targeted agents in the treatment of TNBC.

Recent Findings: TNBC accounts for 15-20% of all breast cancer cases and is associated with worse clinical outcomes. Patients have a higher risk of metastatic recurrence and inferior overall survival compared to other breast cancer subtypes. Cytotoxic chemotherapy has historically been the mainstay of treatment for TNBC. In recent years, we have seen a surge in clinical trials investigating the use of targeted agents in TNBC and now have approval for targeted therapies in select patients. Inhibitors of PARP (olaparib and talazoparib), PD-L1 (atezolizumab) and an antibody drug conjugate targeting Trop-2 (sacituzumab govitecan-hziy) are now approved for the use in select groups of patients with TNBC.

Summary: Various novel targeted agents as monotherapy, dual targeted combinations, and chemotherapy combinations are currently under investigation. The results are promising and may significantly improve patient outcomes in TNBC.
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http://dx.doi.org/10.1007/s12609-021-00416-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386298PMC
September 2021

WEE1 Inhibition in Combination With Targeted Agents and Standard Chemotherapy in Preclinical Models of Pancreatic Ductal Adenocarcinoma.

Front Oncol 2021 25;11:642328. Epub 2021 Mar 25.

Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with high incidences of p53 mutations. AZD1775 (adavosertib, previously MK-1775) is a small molecule WEE1 inhibitor that abrogates the G2M checkpoint and can potentially synergize with DNA damaging therapies commonly used in PDAC treatment. The purpose of this study was to identify combination partners for AZD1775, including standard chemotherapy or targeted agents, in PDAC preclinical models. Low powered preliminary screens demonstrated that two of the four PDX models responded better to the combinations of AZD1775 with irinotecan or capecitabine than to either single agent. Following the screens, two full powered PDAC PDX models of differing p53 status were tested with the combinations of AZD1775 and irinotecan or capecitabine. The combinations of AZD1775 and SN38 or 5-FU were also tested on PDAC cell lines. Cellular proliferation was measured using an IncuCyte Live Cell Imager and apoptosis was measured using a Caspase-Glo 3/7 assay. Flow cytometry was conducted to measure alterations in cell cycle distribution. Western blot analysis was used to determine the effects of the drug combinations on downstream effectors. In PDX models with mutated p53 status, there was significant tumor growth inhibition from the combination of AZD1775 with irinotecan or capecitabine ( ≤ 0.03), while PDX models with wild type p53 did not show anti-tumor synergy from the same combinations ( ≥ 0.08). The combination of AZD1775 with SN38 or 5-FU significantly decreased proliferation in all PDAC cell lines, and enhanced apoptosis in multiple cell lines. Cell cycle distribution was disrupted from the combination of AZD1775 with SN38 or 5-FU which was recorded as G2M arrest and decreased G1 phase. AZD1775 inhibited phospho-CDC2 and increased the expression of H2AX that was either maintained or enhanced after combination with SN38 or 5-FU. The combination of AZD1775 with irinotecan/SN38 or capecitabine/5-FU showed anti-tumor effects and in PDAC models. These results support further investigation for these combination strategies to enhance outcomes for PDAC patients.
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http://dx.doi.org/10.3389/fonc.2021.642328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044903PMC
March 2021

Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes.

Front Immunol 2021 29;12:607282. Epub 2021 Mar 29.

Division of Medical Oncology, School of Medicine, University of Colorado, Aurora, CO, United States.

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2Il2rγSIRPα (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of "responding" patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.
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http://dx.doi.org/10.3389/fimmu.2021.607282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040953PMC
July 2021

Sapanisertib Plus Exemestane or Fulvestrant in Women with Hormone Receptor-Positive/HER2-Negative Advanced or Metastatic Breast Cancer.

Clin Cancer Res 2021 Jun 5;27(12):3329-3338. Epub 2021 Apr 5.

University of Colorado Cancer Center, Aurora, Colorado.

Purpose: This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone receptor-positive (HR)/HER2-negative (HER2) advanced/metastatic breast cancer.

Patients And Methods: Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16).

Results: Overall, 118 patients enrolled in phase IB ( = 24) and II ( = 94). Five patients in phase IB experienced dose-limiting toxicities, at sapanisertib doses of 5 mg every day ( = 4) and 4 mg every day ( = 1); sapanisertib 4 mg every day was the MTD in combination with exemestane or fulvestrant. In phase II, in everolimus-sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%, respectively. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between mutation status and best treatment response (complete + partial response; = 0.0262).

Conclusions: Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausal women with pretreated everolimus-sensitive or everolimus-resistant breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4131DOI Listing
June 2021

Clinical Outcomes for Patients With Metastatic Breast Cancer Treated With Immunotherapy Agents in Phase I Clinical Trials.

Front Oncol 2021 17;11:640690. Epub 2021 Mar 17.

Department of Medicine, University of Colorado Cancer Center, Aurora, CO, United States.

Background: Immuno-oncology (IO) agents have demonstrated efficacy across many tumor types and have led to change in standard of care. In breast cancer, atezolizumab and pembrolizumab were recently FDA-approved in combination with chemotherapy specifically for patients with PD-L1-positive metastatic triple-negative breast cancer (TNBC). However, the single agent PD-1/PD-L1 inhibitors demonstrate only modest single agent efficacy in breast cancer. The purpose of this study was to investigate the efficacy of novel IO agents in patients with metastatic breast cancer (MBC), beyond TNBC, treated in phase I clinical trials at the University of Colorado.

Methods: We performed a retrospective analysis using a database of patients with MBC who received treatment with IO agents in phase I/Ib clinical trials at the University of Colorado Hospital from January 1, 2012 to July 1, 2018. Patient demographics, treatments and clinical outcomes were obtained.

Results: We identified 43 patients treated with an IO agent either as a single agent or in combination. The average age was 53 years; 55.8% had hormone receptor-positive/HER2-negative breast cancer, 39.5% TNBC and 4.7% HER2-positive. Patients received an average of 2 prior lines of chemotherapy (range 0-7) in the metastatic setting. Most patients (72.1%) received IO alone and 27.9% received IO plus chemotherapy. Median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 12.1 months. Patients remaining on study ≥ 6 months (20.9%) were more likely to be treated with chemotherapy plus IO compared to patients with a PFS < 6 months (77.8% v. 14.7%). No differences in number of metastatic sites, prior lines of chemotherapy, breast cancer subtype, absolute lymphocyte count, or LDH were identified between patients with a PFS ≥ 6 months vs. < 6 months.

Conclusions: Our phase I experience demonstrates benefit from IO therapy that was not limited to patients with TNBC and confirms improved efficacy from IO agents in combination with chemotherapy. A subset of patients with MBC treated in phase I clinical trials with an IO agent derived prolonged clinical benefit. Predictors of response to immunotherapy in breast cancer remain uncharacterized and further research is needed to identify these factors.
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http://dx.doi.org/10.3389/fonc.2021.640690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010246PMC
March 2021

Paraneoplastic Encephalitis Associated with Locally Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

J Breast Cancer 2021 Feb;24(1):106-116

Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, USA.

Paraneoplastic neurologic diseases (PND) are rare but can occur in patients with common malignancies including breast cancer. In patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive breast cancer, PND have been reported in association with anti-Yo antibodies and with clinical presentation of paraneoplastic cerebellar degeneration. We describe the case of a woman with progressively altered mental status and seizures, ultimately requiring admission. Based on her clinical presentation, imaging findings, and evidence of neural-directed antibodies in her serum and cerebrospinal fluid, she was diagnosed with paraneoplastic limbic encephalitis (LE) due to an underlying HR-negative, HER2-positive breast cancer. She showed a transient response to immunosuppression but had more significant improvement after surgical resection and initiation of chemotherapy along with HER2-directed therapy. To the best of our knowledge, this is the first documented case of paraneoplastic LE in a patient with HR-negative, HER2-positive breast cancer likely caused by the production of an unclassified anti-neuronal antibody.
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http://dx.doi.org/10.4048/jbc.2021.24.e2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920863PMC
February 2021

A phase I pharmacokinetic and safety study of Paclitaxel Injection Concentrate for Nano-dispersion (PICN) alone and in combination with carboplatin in patients with advanced solid malignancies and biliary tract cancers.

Cancer Chemother Pharmacol 2021 06 26;87(6):779-788. Epub 2021 Feb 26.

Division of Medical Oncology, Department of Medicine, Developmental Therapeutics Program, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8101, Aurora, CO, 80045, USA.

Purpose: Paclitaxel injection concentrate for nano-dispersion (PICN) is a Cremophor-free, nanotechnology-driven paclitaxel formulation. This phase I study examined the safety, tolerability, pharmacokinetics and maximum tolerated dose (MTD) of PICN alone and in combination with carboplatin. Its early efficacy in unresectable biliary tract cancers (BTCs) was also evaluated.

Methods: This multi-center study comprised two parts. Part A contained a dose-escalation cohort following "3 + 3" design using PICN monotherapy in advanced solid tumors (Part A1); Part A2 dose-expansion cohort was then conducted in advanced BTCs due to observed efficacy in Part A1. Part B1 and B2 evaluated escalating dose of PICN with carboplatin in advanced solid tumors. PICN was administered as a 30 min-infusion every 3 weeks without pre-medications for hypersensitivity reactions.

Results: Thirty-six patients received PICN monotherapy in Part A and 21 received PICN plus carboplatin in Part B. The MTD of PICN was determined to be 295 mg/m both as a monotherapy and in combination with carboplatin at AUC 5. Dose-proportional exposure in paclitaxel C and AUC was observed overdose range from 175 to 325 mg/m for PICN monotherapy and its combination with carboplatin. Carboplatin did not alter PICN exposure. Clinically significant toxicities mainly include neutropenia and peripheral neuropathy. PICN monotherapy yielded a response rate of 20% in unresectable BTCs.

Conclusion: This study demonstrated the safety and stable pharmacokinetics of PICN as a monotherapy and in combination with carboplatin. Single-agent PICN showed promising antitumor activity in advanced BTCs, warranting further studies to investigate its role in gastrointestinal cancers.
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http://dx.doi.org/10.1007/s00280-021-04235-zDOI Listing
June 2021

Real-world evidence from a University Hospital system regarding the uptake of adjuvant pertuzumab and/or neratinib before and after their FDA approval.

Breast Cancer Res Treat 2021 Jun 24;187(3):883-891. Epub 2021 Feb 24.

Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA.

Purpose: Adjuvant pertuzumab and neratinib are independently FDA-approved for treatment of early-stage HER2-positive breast cancer in combination with or following trastuzumab for one year, respectively. Both agents reduce the risk of recurrence; however, the absolute benefit is modest for many patients with added risk of adverse effects. The purpose of this study was to evaluate the clinical use of adjuvant pertuzumab and neratinib in patients with early-stage HER2-positive breast cancer.

Methods: Patients diagnosed with stage I-III HER2-positive breast cancer treated with trastuzumab at four University of Colorado Health hospitals between July 2016 and April 2019 were identified. Patient demographics, cancer stage, treatment, and administration of pertuzumab and/or neratinib were obtained.

Results: We identified a total of 350 patients who received adjuvant trastuzumab for stage I-III HER2-positive breast cancer; 253 (73.1%) had tumors that were ≥ T2 or node-positive disease. The rate of adjuvant pertuzumab use increased following FDA approval; pertuzumab was administered to the majority of patients with node-positive HER2-positive breast cancer. The use of adjuvant pertuzumab was associated with younger age, premenopausal status, and node-positive disease. Rates of administration of adjuvant neratinib were lower, with only 15.2% of patients receiving this therapy within 3 months of completing adjuvant trastuzumab.

Conclusion: In our cohort of patients treated within a diverse healthcare network, the majority of patients with node-positive HER2-positive breast cancer received adjuvant pertuzumab following FDA approval. The use of adjuvant neratinib was less common, potentially as a result of adverse effects, prolongation of therapy, previous administration of adjuvant pertuzumab, and modest benefit.
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http://dx.doi.org/10.1007/s10549-021-06132-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197701PMC
June 2021

New Persistent Opioid and Benzodiazepine Use After Curative-Intent Treatment in Patients With Breast Cancer.

J Natl Compr Canc Netw 2021 01 6;19(1):29-38. Epub 2021 Jan 6.

Division of Medical Oncology, Department of Medicine, and.

Background: Opioid and benzodiazepine use and abuse is a national healthcare crisis to which patients with cancer are particularly vulnerable. Long-term use and risk factors for opioid and benzodiazepine use in patients with breast cancer is poorly characterized.

Methods: We conducted a retrospective population-based study of patients with breast cancer diagnosed between 2008 and 2015 undergoing curative-intent treatment identified through the SEER-Medicare linked database. Primary outcomes were new persistent opioid use and new persistent benzodiazepine use. Factors associated with new opioid and benzodiazepine use were investigated by univariate and multivariable logistic regression.

Results: Among opioid-naïve patients, new opioid use was observed in 22,418 (67.4%). Of this group, 611 (2.7%) developed persistent opioid use at 3 months and 157 (0.7%) at 6 months after treatment. Risk factors for persistent use at 3 and 6 months included stage III disease (odds ratio [OR], 2.16; 95% CI, 1.49-3.12, and OR, 3.48; 95% CI, 1.58-7.67), surgery plus chemotherapy (OR, 1.44; 95% CI, 1.10-1.88, and OR, 2.28; 95% CI, 1.40-3.71), surgery plus chemoradiation therapy (OR, 1.47; 95% CI, 1.10-1.96, and OR, 2.34; 95% CI, 1.38-3.96), and initial tramadol use (OR, 2.66; 95% CI, 2.05-3.46, and OR, 3.12; 95% CI, 1.93-5.04). Among benzodiazepine-naïve patients, new benzodiazepine use was observed in 955 (10.3%), and 111 (11.6%) developed new persistent use at 3 months. Tamoxifen use was statistically significantly associated with new persistent benzodiazepine use at 3 months.

Conclusions: A large percentage of patients receiving curative-intent treatment of breast cancer were prescribed new opioids; however, only a small number developed new persistent opioid use. In contrast, a smaller proportion of patients received a new benzodiazepine prescription; however, new persistent use after completion of treatment was more likely and particularly related to concurrent treatment with tamoxifen.
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http://dx.doi.org/10.6004/jnccn.2020.7612DOI Listing
January 2021

RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer.

BMC Cancer 2020 Nov 4;20(1):1063. Epub 2020 Nov 4.

Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, MS8117, Aurora, CO, 80045, USA.

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear β-catenin signaling. The purpose of this study was to evaluate the ability of β-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC.

Methods: Treatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4 T1 TNBC cell line. Humanized BALB/c-Rag2Il2rγSIRPα (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells.

Results: The addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4 T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p < 0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p < 0.01).

Conclusions: Conclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.
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http://dx.doi.org/10.1186/s12885-020-07500-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641792PMC
November 2020

Clinical outcomes of breast cancer patients treated in phase I clinical trials at University of Colorado Cancer Center.

Cancer Med 2020 12 16;9(23):8801-8808. Epub 2020 Oct 16.

Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Patients with metastatic breast cancer (MBC) refractory to standard of care therapies have a poor prognosis. The purpose of this study was to assess patient characteristics and clinical outcomes for patients with MBC treated on phase I clinical trials. We performed a retrospective review of all patients with MBC who were enrolled in phase I clinical trials at the University of Colorado Cancer Center from January 2012 to June 2018. A total of 208 patients were identified. Patients had a mean age of 57 years and received on average 2.1 (range 0-10) prior lines of chemotherapy. The majority of patients had hormone receptor-positive/HER2-negative breast cancer (58.6%) and 30.3% had triple-negative breast cancer. The median progression free survival (PFS) was 2.8 months (95% CI, 2.3-3.9) and median overall survival (OS) was 11.5 months (95% CI, 9.6-13.2). Independent factors associated with longer PFS in multivariable analysis were treatment in a breast cancer-selective trial or cohort (p = 0.016), age >50 years (p = 0.002), and ≤2 prior lines of chemotherapy in the metastatic setting (p = 0.025). Phase I clinical trials remain a valuable option for select patients with MBC and enrollment should be encouraged when available.
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http://dx.doi.org/10.1002/cam4.3487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724484PMC
December 2020

Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer.

Breast Cancer Res Treat 2020 Nov 14;184(1):53-62. Epub 2020 Aug 14.

Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd, SCCT Mezzanine MS 35, Los Angeles, CA, 90048, USA.

Purpose: Vantictumab is a monoclonal antibody that binds to frizzled (FZD) receptors and inhibits canonical WNT signaling. This phase Ib dose escalation study enrolled patients with locally recurrent or metastatic HER2-negative breast cancer who were treated with weekly paclitaxel in combination with escalating doses of vantictumab.

Methods: Patients were enrolled in dose escalation cohorts treated with weekly paclitaxel 90 mg/m on days 1, 8 and 15 in combination with vantictumab 3.5-14 mg/kg days 1 and 15 or 3-8 mg/kg day 1 of every 28-day cycle. Primary endpoints were safety, dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics, efficacy and an exploratory biomarker analysis.

Results: Forty-eight female patients with a mean age of 54 were enrolled. The majority (66.6%) received prior chemotherapy for recurrent or metastatic disease; 45.8% were hormone receptor (HR)-positive, HER2-negative and 54.2% triple-negative. The most frequent adverse events related to any study treatment were nausea (54.2%), alopecia (52.1%), fatigue (47.9%), and peripheral neuropathy (43.8%). No DLTs occurred; however, 6 patients experienced fractures outside of the DLT window. The overall response rate was 31.3% and the clinical benefit rate was 68.8%. A 6-gene WNT pathway signature showed significant association with progression-free survival (PFS) and overall survival (OS) for the biomarker high versus biomarker low groups (PFS: p = 0.029 and OS: p = 0.00045, respectively).

Conclusions: The combination of vantictumab and weekly paclitaxel was generally well tolerated with promising efficacy; however, the incidence of fractures limits future clinical development of this particular WNT inhibitor in metastatic breast cancer.

Clinical Trial Registration: ClinicalTrials.gov registration: NCT01973309.
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http://dx.doi.org/10.1007/s10549-020-05817-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572714PMC
November 2020

Survival and clinical outcomes of patients with ovarian cancer who were treated on phase 1 clinical trials.

Cancer 2020 10 22;126(19):4289-4293. Epub 2020 Jul 22.

Department of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado.

Background: Patients with ovarian cancer who are enrolled on phase 1 trials typically have platinum-resistant and heavily pretreated disease, with a poor prognosis. In the current study, the authors assessed prognostic factors and survival in women with recurrent ovarian cancer who were treated on phase 1 clinical trials.

Methods: The authors performed a retrospective analysis of patients treated from 2008 through 2018 at the University of Colorado Cancer Center. Patient characteristics and treatment and toxicity-related survival data were assessed. Descriptive statistics and Cox proportional hazards models were used to identify risk factors associated with survival time.

Results: A total of 132 patients were treated on phase 1 clinical trials. Patients had a median age of 59 years (range, 33-88 years) with a median of 5.5 previous chemotherapy lines (range, 1-13 lines). Of the 132 patients, 53 (40%) were treated on multiple phase 1 trials with a median of 1 (range, 0-5) prior phase 1 trial. The overall response rate was 14.7%. The median overall survival was 11.3 months (95% CI, 9.1-13.4 months). Two patients died on trial due to progression of disease whereas no patients died of treatment-related toxicity. Independent risk factors found to be predictive of shorter survival were an elevated cancer antigen 125 (CA 125) level (hazard ratio [HR], 2.8; 95% CI, 1.6-5.2) and albumin <3.5 g/dL (HR, 2.5; 95% CI, 1.65-3.79). A body mass index >25 kg/m was predictive of longer survival (HR, 0.65; 95% CI, 0.44-0.96).

Conclusions: In the current single-institution series, patients with heavily pretreated ovarian cancer who were treated on phase 1 clinical trials experienced a median overall survival of 11.3 months. When available, phase 1 clinical trials represent a reasonable treatment option for patients with heavily pretreated ovarian cancer with a preserved performance status.
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http://dx.doi.org/10.1002/cncr.33073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723337PMC
October 2020

Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors.

Clin Cancer Res 2020 09 15;26(17):4633-4642. Epub 2020 May 15.

University of Colorado Cancer Center, Aurora, Colorado.

Purpose: The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors.

Experimental Design: TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD).

Results: The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia.

Conclusions: The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib , resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864382PMC
September 2020

Wee1 Inhibition Enhances the Anti-Tumor Effects of Capecitabine in Preclinical Models of Triple-Negative Breast Cancer.

Cancers (Basel) 2020 Mar 19;12(3). Epub 2020 Mar 19.

Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, Aurora, CO 80045, USA.

Triple-negative breast cancer (TNBC) is an aggressive subtype defined by lack of hormone receptor expression and non-amplified HER2. Adavosertib (AZD1775) is a potent, small-molecule, ATP-competitive inhibitor of the Wee1 kinase that potentiates the activity of many DNA-damaging chemotherapeutics and is currently in clinical development for multiple indications. The purpose of this study was to investigate the combination of AZD1775 and capecitabine/5FU in preclinical TNBC models. TNBC cell lines were treated with AZD1775 and 5FU and cellular proliferation was assessed in real-time using IncuCyte Live Cell Analysis. Apoptosis was assessed via the Caspase-Glo 3/7 assay system. Western blotting was used to assess changes in expression of downstream effectors. TNBC patient-derived xenograft (PDX) models were treated with AZD1775, capecitabine, or the combination and assessed for tumor growth inhibition. From the initial PDX screen, two of the four TNBC PDX models demonstrated a better response in the combination treatment than either of the single agents. As confirmation, two PDX models were expanded for statistical comparison. Both PDX models demonstrated a significant growth inhibition in the combination versus either of the single agents. (TNBC012, < 0.05 combo vs. adavosertib or capecitabine, TNBC013, < 0.01 combo vs. adavosertib or capecitabine.) An enhanced anti-proliferative effect was observed in the adavosertib/5FU combination treatment as measured by live cell analysis. An increase in apoptosis was observed in two of the four cell lines in the combination when compared to single-agent treatment. Treatment with adavosertib as a single agent resulted in a decrease in p-CDC2 in a dose-dependent manner that was also observed in the combination treatment. An increase in γH2AX in two of the four cell lines tested was also observed. No significant changes were observed in Bcl-xL following treatment in any of the cell lines. The combination of adavosertib and capecitabine/5FU demonstrated enhanced combination effects both in vitro and in vivo in preclinical models of TNBC. These results support the clinical investigation of this combination in patients with TNBC, including those with brain metastasis given the CNS penetration of both agents.
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http://dx.doi.org/10.3390/cancers12030719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140086PMC
March 2020

Nab-paclitaxel and atezolizumab for the treatment of PD-L1-positive, metastatic triple-negative breast cancer: review and future directions.

Expert Rev Precis Med Drug Dev 2020 20;5(2):59-65. Epub 2020 Feb 20.

Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, United States of America.

Introduction: Breast cancer is the most common malignancy in women in the United States and triple-negative breast cancer (TNBC) accounts for 15-20%. The standard of care for metastatic TNBC has been limited to cytotoxic chemotherapy with modest efficacy. TNBC is associated with high levels of tumor-infiltrating lymphocytes and PD-L1 expression, supporting the investigation of immune checkpoint inhibitors in this breast cancer subtype.

Areas Covered: This review summarizes the clinical data supporting the use of atezolizumab and nab-paclitaxel in the treatment of metastatic PD-L1-positive TNBC. It examines the pharmacology and toxicity profile of the combination in patients with metastatic TNBC.

Expert Opinion: The addition of atezolizumab to nab-paclitaxel prolonged progression-free survival in both the intention-to-treat and PD-L1-positive subgroups in the first line setting in patients with metastatic TNBC. The IMpassion 130 trial led to FDA-approval of this combination in patients with PD-L1-positive, metastatic TNBC and represents the first approval of immunotherapy for TNBC. This work supports ongoing investigations of other immunotherapy combinations in TNBC, predictive biomarker development and immunotherapy in patients with early stage TNBC. Immunotherapy combinations in TNBC have the potential to lead to improved survival in this group of patients with high risk disease.
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http://dx.doi.org/10.1080/23808993.2020.1730694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080186PMC
February 2020

First-in-Class Phosphorylated-p68 Inhibitor RX-5902 Inhibits β-Catenin Signaling and Demonstrates Antitumor Activity in Triple-Negative Breast Cancer.

Mol Cancer Ther 2019 11 5;18(11):1916-1925. Epub 2019 Sep 5.

University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of β-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on β-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed. Gene expression profiling was used in sensitive and resistant cell lines with pathway analysis to explore pathways associated with sensitivity to RX-5902. The activity of RX-5902 was confirmed in cell line and patient-derived tumor xenograft (PDX) models. RX-5902 demonstrated potent antiproliferative activity against TNBC cell lines with an average IC of 56 nmol/L in sensitive cell lines. RX-5902 treatment resulted in the induction of apoptosis, G-M cell-cycle arrest, and aneuploidy in a subset of cell lines. RX-5902 was active against TNBC PDX models, and treatment resulted in a decrease in nuclear β-catenin. RX-5902 exhibited dose-proportional pharmacokinetics and plasma and tumor tissue in nude mice. Pathway analysis demonstrated an increase in the epithelial-to-mesenchymal transformation (EMT), TGFβ, and Wnt/β-catenin pathways associated with sensitivity to RX-5902. RX-5902 is active against and preclinical models of TNBC. Target engagement was confirmed with decreases in nuclear β-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-1334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825586PMC
November 2019

Sacituzumab govitecan: breakthrough targeted therapy for triple-negative breast cancer.

Expert Rev Anticancer Ther 2019 08 19;19(8):673-679. Epub 2019 Aug 19.

Division of Medical Oncology, University of Colorado Cancer Center , Aurora , CO , USA.

: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with an increased risk of recurrence and cancer-related death. Unlike hormone receptor-positive or HER2-positive breast cancers, there are limited targeted therapies available to treat TNBC and cytotoxic chemotherapy remains the mainstay of treatment. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate targeting Trop-2 expressing cells and selectively delivering SN-38, an active metabolite of irinotecan. : This review covers the mechanism of action, safety and efficacy of sacituzumab govitecan in patients with previously treated, metastatic TNBC. Additionally, efficacy data in other epithelial malignancies is included based on a PubMed search for 'sacituzumab govitecan' and 'clinical trial'. : Sacituzumab govitecan has promising anti-cancer activity in patients with metastatic TNBC previously treated with at least two prior lines of systemic therapy based on a single arm Phase I/II clinical trial. A confirmatory Phase III randomized clinical trial is ongoing. Sacituzumab govitecan has a manageable side effect profile, with the most common adverse events being nausea, neutropenia, and diarrhea. The activity of sacituzumab govitecan likely extends beyond TNBC with promising early efficacy data in many other epithelial cancers, including hormone receptor-positive breast cancer.
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http://dx.doi.org/10.1080/14737140.2019.1654378DOI Listing
August 2019

Combination of Trastuzumab Emtansine and Stereotactic Radiosurgery Results in High Rates of Clinically Significant Radionecrosis and Dysregulation of Aquaporin-4.

Clin Cancer Res 2019 07 2;25(13):3946-3953. Epub 2019 Apr 2.

Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado.

Purpose: Patients with human EGFR2-positive (HER2) breast cancer have a high incidence of brain metastases, and trastuzumab emtansine (T-DM1) is often employed. Stereotactic radiosurgery (SRS) is frequently utilized, and case series report increased toxicity with combination SRS and T-DM1. We provide an update of our experience of T-DM1 and SRS evaluating risk of clinically significant radionecrosis (CSRN) and propose a mechanism for this toxicity.

Experimental Design: Patients with breast cancer who were ≤45 years regardless of HER2 status or had HER2 disease regardless of age and underwent SRS for brain metastases were included. Rates of CSRN, SRS data, and details of T-DM1 administration were recorded. Proliferation and astrocytic swelling studies were performed to elucidate mechanisms of toxicity.

Results: A total of 45 patients were identified; 66.7% were HER2, and 60.0% were ≤ 45 years old. Of the entire cohort, 10 patients (22.2%) developed CSRN, 9 of whom received T-DM1. CSRN was observed in 39.1% of patients who received T-DM1 versus 4.5% of patients who did not. Receipt of T-DM1 was associated with a 13.5-fold ( = 0.02) increase in CSRN. Mechanistically, T-DM1 targeted reactive astrocytes and increased radiation-induced cytotoxicity and astrocytic swelling via upregulation of Aquaporin-4 (Aqp4).

Conclusions: The strong correlation between development of CSRN after SRS and T-DM1 warrants prospective studies controlling for variations in timing of T-DM1 and radiation dosing to further stratify risk of CSRN and mitigate toxicity. Until such studies are completed, we advise caution in the combination of SRS and T-DM1.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751332PMC
July 2019

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer.

N Engl J Med 2019 02;380(8):741-751

From the Massachusetts General Hospital Cancer Center (A.B., S.J.I.) and Dana-Farber Cancer Institute (S.M.T.), Harvard Medical School, Boston; Vanderbilt-Ingram Cancer Center, Nashville (I.A.M., V.G.A.); Weill Cornell Medical College (L.T.V.) and New York-Presbyterian-Columbia University Irving Medical Center (K.K.), New York; University of Colorado Cancer Center, Aurora (J.R.D.); Texas Oncology, Baylor University Medical Center, US Oncology, Dallas (J.O.); Orlando Health University of Florida Health Cancer Center, Orlando (R.L.M., N.C.S.); Yale University School of Medicine, New Haven, CT (A.D.S.); University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco (H.S.R.); Immunomedics, Morris Plains, NJ (D.M.G., R.I., S.W., R.M.S., W.A.W.); and AIS Consulting, Ann Arbor, MI (A.M.S.).

Background: Standard chemotherapy is associated with low response rates and short progression-free survival among patients with pretreated metastatic triple-negative breast cancer. Sacituzumab govitecan-hziy is an antibody-drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors.

Methods: We conducted a phase 1/2 single-group, multicenter trial involving patients with advanced epithelial cancers who received sacituzumab govitecan-hziy intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxic effects. A total of 108 patients received sacituzumab govitecan-hziy at a dose of 10 mg per kilogram of body weight after receiving at least two previous anticancer therapies for metastatic triple-negative breast cancer. The end points included safety; the objective response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), which was assessed locally; the duration of response; the clinical benefit rate (defined as a complete or partial response or stable disease for at least 6 months); progression-free survival; and overall survival. Post hoc analyses determined the response rate and duration, which were assessed by blinded independent central review.

Results: The 108 patients with triple-negative breast cancer had received a median of 3 previous therapies (range, 2 to 10). Four deaths occurred during treatment; 3 patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall survival was 13.0 months (95% CI, 11.2 to 13.7).

Conclusions: Sacituzumab govitecan-hziy was associated with durable objective responses in patients with heavily pretreated metastatic triple-negative breast cancer. Myelotoxic effects were the main adverse reactions. (Funded by Immunomedics; IMMU-132-01 ClinicalTrials.gov number, NCT01631552.).
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http://dx.doi.org/10.1056/NEJMoa1814213DOI Listing
February 2019

Atezolizumab Plus nab-Paclitaxel in the Treatment of Metastatic Triple-Negative Breast Cancer With 2-Year Survival Follow-up: A Phase 1b Clinical Trial.

JAMA Oncol 2019 03;5(3):334-342

Carolina BioOncology Institute, Huntersville, North Carolina.

Importance: The humanized monoclonal antibody atezolizumab targets programmed death-ligand 1 and has demonstrated durable single-agent activity in a subset of metastatic triple-negative breast cancers. To extend the observed activity, combinatorial approaches are being tested with standard cytotoxic chemotherapies known to induce immunogenic tumor cell death.

Objective: To examine the safety, tolerability, and preliminary clinical activity of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancers.

Design, Setting, And Participants: This phase 1b multicohort study enrolled 33 women with stage IV or locally recurrent triple-negative breast cancers and 0 to 2 lines of prior chemotherapy in the metastatic setting from December 8, 2014, to April 30, 2017, at 11 sites in the United States. The median follow-up was 24.4 months (95% CI, 22.1-28.8 months).

Interventions: Patients received concurrent intravenous atezolizumab and intravenous nab-paclitaxel (minimum 4 cycles).

Main Outcomes And Measures: The primary end point was safety and tolerability. Secondary end points included best overall response rate by Response Evaluation Criteria in Solid Tumors, version 1.1; objective response rate; duration of response; disease control rate; progression-free survival; overall survival; and biomarker analyses.

Results: The 33 women had a median age of 55 years (range, 32-84 years) and received 1 or more doses of atezolizumab. All patients (100%) experienced at least 1 treatment-related adverse event, 24 patients (73%) experienced grade 3/4 adverse events, and 7 patients (21%) had grade 3/4 adverse events of special interest. No deaths were related to study treatment. The objective response rate was 39.4% (95% CI, 22.9%-57.9%), and the median duration of response was 9.1 months (95% CI, 2.0-20.9 months). The disease control rate was 51.5% (95% CI, 33.5%-69.2%). Median progression-free survival and overall survival were 5.5 months (95% CI, 5.1-7.7 months) and 14.7 months (95% CI, 10.1-not estimable), respectively. Concurrent nab-paclitaxel neither significantly changed biomarkers of the tumor immune microenvironment (programmed death-ligand 1, tumor-infiltrating lymphocytes, CD8) nor impaired atezolizumab systemic immune activation (expansion of proliferating CD8+ T cells, increase of CXCL10 chemokine).

Conclusions And Relevance: In this phase 1b trial for metastatic triple-negative breast cancers, the combination of atezolizumab plus nab-paclitaxel had a manageable safety profile. Antitumor responses were observed, including in patients previously treated with a taxane.

Trial Registration: ClinicalTrials.gov identifier: NCT01633970.
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http://dx.doi.org/10.1001/jamaoncol.2018.5152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439843PMC
March 2019

A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors.

Invest New Drugs 2019 06 19;37(3):461-472. Epub 2018 Sep 19.

University of Michigan, Ann Arbor, MI, USA.

Purpose Navicixizumab (OMP-305B83) is a bispecific antibody that inhibits delta-like ligand 4 and vascular endothelial growth factor. This Phase 1a trial assessed escalating doses of navicixizumab in refractory solid tumors patients. Design A 3 + 3 dose escalation design was used followed by the treatment of additional patients in an expansion cohort. Study objectives were determination of the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, immunogenicity and efficacy. Results Sixty-six patients were treated once every 3 weeks in 8 dose-escalation cohorts (0.5, 1, 2.5, 3.5, 5, 7.5, 10, and 12.5 mg/kg) and an expansion cohort (7.5 mg/kg). The median age was 60 years and 68% of the patients were female. The most commonly enrolled tumor types were ovarian (12), colorectal (11) and breast, pancreatic, uterine and endometrial (4 each) cancers. As only 1 dose limiting toxicity occurred, the maximum tolerated dose was not reached, but 7.5 mg/kg was chosen as the dose for the expansion cohort. The treatment related adverse events (≥15% of patients) were hypertension (57.6%), headache (28.8%), fatigue (25.8%), and pulmonary hypertension (18.2%). Pulmonary hypertension was mostly asymptomatic at doses ≤5 mg/kg (6 Gr1, 1 Gr2), but was more severe at higher doses (4 Gr2, 1 Gr3). Navicixizumab's half-life was 11.4 days and there was a moderate (29%) incidence of anti-drug antibody formation. Four patients (3 ovarian cancer, 1 uterine carcinosarcoma) had a partial response and 17 patients had stable disease. Nineteen patients had a reduction in the size of their target lesions including 7/11 patients with ovarian cancer. Four patients remained on study for >300 days and 2 of these patients were on study for >500 days. Conclusions Navicixizumab can be safely administered with manageable toxicities and these data showed preliminary signs of antitumor activity in multiple tumor types, but was most promising in ovarian cancer. As a result these data justify its continued development in combination Phase 1b clinical trials.
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http://dx.doi.org/10.1007/s10637-018-0665-yDOI Listing
June 2019

A Phase I Dose-Escalation Study of Linsitinib (OSI-906), a Small-Molecule Dual Insulin-Like Growth Factor-1 Receptor/Insulin Receptor Kinase Inhibitor, in Combination with Irinotecan in Patients with Advanced Cancer.

Oncologist 2018 12 23;23(12):1409-e140. Epub 2018 Aug 23.

University of Colorado Cancer Center, Aurora, Colorado, USA.

Lessons Learned: The maximum tolerated dose of the combination of linsitinib and irinotecan is linsitinib 450 mg daily on days 1-3 every 7 days and irinotecan 125 mg/m days 1 and 8 of a 21-day cycle.The adverse effects associated with the combination are not significantly increased beyond what is expected of each drug as a single agent.Multiple negative trials of insulin-like growth factor-1 receptor inhibitors performed in unselected patient populations led to the early discontinuation of linistinib development and this trial.Earlier integration of assessment of potential predictive biomarkers into clinical trials, as was planned in this study, is vital to the development of targeted therapies in oncology.

Background: This phase I dose-escalation study was designed to evaluate the safety and tolerability of the combination of irinotecan and insulin-like growth factor-1 receptor (IGF-1R) inhibitor linsitinib in patients with advanced cancer refractory to standard therapy.

Methods: Dose escalation in three specified dose levels was performed according to a standard 3 + 3 design. Dose levels were as follows: (a) linsitinib 400 mg and irinotecan 100 mg/m, (b) linsitinib 450 mg and irinotecan 100 mg/m, and (c) linsitinib 450 mg and irinotecan 125 mg/m. Linisitinib was administered once daily on days 1-3, 8-10, and 15-17, and irinotecan on days 1 and 8. Assessment of a candidate predictive biomarker was planned in all patients, with further evaluation in an expansion cohort of advanced colorectal cancer.

Results: A total of 17 patients were treated, with 1 patient in both cohort 2 and 3 experiencing dose-limiting toxicity. Linsitinib 450 mg and irinotecan 125 mg/m was the maximum tolerated dose. Sixteen (94%) patients experienced at least one treatment-related adverse event. Neutropenia was the only grade >3 toxicity (4%). No significant hyperglycemia or QT interval prolongation was noted. No objective responses were observed; 47% ( = 8) had stable disease with median duration of 5.25 months.

Conclusion: Although the combination was determined safe, the study was halted due to termination of linsitinib development, and biomarker testing was not performed.
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http://dx.doi.org/10.1634/theoncologist.2018-0315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292546PMC
December 2018

A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer.

Breast Cancer Res 2018 08 2;20(1):82. Epub 2018 Aug 2.

Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.

Background: Triple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype with limited treatment options. ENMD-2076 is a small-molecule inhibitor of Aurora and angiogenic kinases with proapoptotic and antiproliferative activity in preclinical models of TNBC.

Methods: This dual-institution, single-arm, two-stage, phase II clinical trial enrolled patients with locally advanced or metastatic TNBC previously treated with one to three prior lines of chemotherapy in the advanced setting. Patients were treated with ENMD-2076 250 mg orally once daily with continuous dosing in 4-week cycles until disease progression or unacceptable toxicity occurred. The primary endpoint was 6-month clinical benefit rate (CBR), and secondary endpoints included progression-free survival, pharmacokinetic profile, safety, and biologic correlates in archival and fresh serial tumor biopsies in a subset of patients.

Results: Forty-one patients were enrolled. The 6-month CBR was 16.7% (95% CI, 6-32.8%) and included two partial responses. The 4-month CBR was 27.8% (95% CI, 14-45.2%), and the average duration of benefit was 6.5 cycles. Common adverse events included hypertension, fatigue, diarrhea, and nausea. Treatment with ENMD-2076 resulted in a decrease in cellular proliferation and microvessel density and an increase in p53 and p73 expression, consistent with preclinical observations.

Conclusions: Single-agent ENMD-2076 treatment resulted in partial response or clinical benefit lasting more than 6 months in 16.7% of patients with pretreated, advanced, or metastatic TNBC. These results support the development of predictive biomarkers using archival and fresh tumor tissue, as well as consideration of mechanism-based combination strategies.

Trial Registration: ClinicalTrials.gov, NCT01639248 . Registered on July 12, 2012.
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http://dx.doi.org/10.1186/s13058-018-1014-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090978PMC
August 2018

Dual compartmental targeting of cell cycle and angiogenic kinases in colorectal cancer models.

Anticancer Drugs 2018 10;29(9):827-838

Division of Medical Oncology, School of Medicine.

Cancer is a disease caused by several factors characterized by uncontrolled cell division, growth, and survival. ENMD-2076, is a novel orally active small molecule multikinase inhibitor targeting angiogenesis, proliferation, and the cell cycle. It is selectively active against the mitotic kinases aurora A and B, and kinases responsible for angiogenesis including VEGFR2/KDR and FGFR1 and 2. ENMD-2076 has been shown to inhibit tumor growth and prevent angiogenesis in vitro and in vivo in preclinical cancer models. Moreover, in a phase I trial, ENMD-2076 was well tolerated, exhibited a linear pharmacokinetic profile, and showed a promising antitumor activity in a number of solid tumors. In this study, we show that ENMD-2076 has antiproliferative effects, causes cell cycle arrest, and has activity in preclinical models of colorectal cancer (CRC), including patient-derived xenograft (PDX) models. Forty-seven human CRC cell lines were exposed in vitro to ENMD-2076 and analyzed for effects on cell cycle, apoptosis, and downstream effector proteins. The drug was then tested against 20 human CRC PDX models to further evaluate in-vivo antitumor activity. We show that ENMD-2076 exhibits a broad range of activity against a large panel of CRC cell lines with varying molecular characteristics. Mechanistically, ENMD-2076 exposure resulted in a G2/M cell cycle arrest, an increase in aneuploidy, and cell death in responsive cell lines. In addition, ENMD-2076 treatment resulted in a promising antitumor activity in CRC PDX models. These results support the continued development of ENMD-2076 in CRC including further exploration of rational combinations.
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http://dx.doi.org/10.1097/CAD.0000000000000673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143222PMC
October 2018

Efficacy and Molecular Mechanisms of Differentiated Response to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Models of p53-Mutated Triple-Negative Breast Cancer.

Front Oncol 2017 15;7:94. Epub 2017 May 15.

Department of Medicine, Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Purpose: Triple-negative breast cancer (TNBC) is a subtype associated with poor prognosis and for which there are limited therapeutic options. The purpose of this study was to evaluate the efficacy of ENMD-2076 in p53-mutated TNBC patient-derived xenograft (PDX) models and describe patterns of terminal cell fate in models demonstrating sensitivity, intrinsic resistance, and acquired resistance to ENMD-2076.

Experimental Design: p53-mutated, TNBC PDX models were treated with ENMD-2076 and evaluated for mechanisms of sensitivity or resistance to treatment. Correlative tissue testing was performed on tumor tissue to assess for markers of proliferation, apoptosis, senescence, and pathways of resistance after treatment and at the time of acquired resistance.

Results: Sensitivity to ENMD-2076 200 mg/kg daily was associated with induction of apoptosis while models exhibiting intrinsic or acquired resistance to treatment presented with a senescent phenotype. Response to ENMD-2076 was accompanied by an increase in p53 and p73 levels, even within the background of mutant p53. Treatment with ENMD-2076 resulted in a decrease in pAurA and an increase in pHH3. We observed a TNBC subtype switch from the luminal androgen receptor to the basal-like subtype at acquired resistance.

Conclusion: ENMD-2076 has antitumor activity in preclinical models of p53-mutated TNBC. Increased levels of p53 and p73 correlated with sensitivity whereas senescence was associated with resistance to ENMD-2076. The novel finding of a TNBC subtype switch at time of acquired resistance may provide mechanistic insights into the biologic effects of selective pressure of anticancer treatments on TNBC. ENMD-2076 is currently being evaluated in a Phase 2 clinical trial in patients with metastatic, previously treated TNBC where these biologic correlates can be further explored.
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http://dx.doi.org/10.3389/fonc.2017.00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430301PMC
May 2017

Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer.

J Clin Oncol 2017 Jul 14;35(19):2141-2148. Epub 2017 Mar 14.

Aditya Bardia, Steven J. Isakoff, and Dejan Juric, Massachusetts General Hospital Cancer Center; Aditya Bardia, Steven J. Isakoff, Dejan Juric, and Sara M. Tolaney, Harvard Medical School; Sara M. Tolaney, Dana-Farber Cancer Institute, Boston, MA; Ingrid A. Mayer, Vandana Abramson, and Jordan Berlin, Vanderbilt-Ingram Cancer Center, Nashville, TN; Jennifer R. Diamond and Wells A. Messersmith, University of Colorado Cancer Center, Aurora, CO; Rebecca L. Moroose and Nikita C. Shah, University of Florida Health Cancer Center, Orlando, FL; Alexander N. Starodub, Indiana University Health Center for Cancer Care, Goshen, IN; Joyce O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center; Joyce O'Shaughnessy, US Oncology, Dallas, TX; Kevin Kalinsky, Columbia University Herbert Irving Comprehensive Cancer Center; Allyson J. Ocean and Linda T. Vahdat, Weill Cornell Medicine, New York, NY; Michael Guarino, Helen F. Graham Cancer Center, Newark, DE; William A. Wegener, Pius Maliakal, Robert M. Sharkey, Serengulam V. Govindan, and David M. Goldenberg, Immunomedics, Morris Plains, NJ.

Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.
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http://dx.doi.org/10.1200/JCO.2016.70.8297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559902PMC
July 2017
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