Publications by authors named "Apostolia M Tsimberidou"

156 Publications

Preclinical Development and First-in-Human Study of KA2507, a Selective and Potent Inhibitor of Histone Deacetylase 6, for Patients with Refractory Solid Tumors.

Clin Cancer Res 2021 May 4. Epub 2021 May 4.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Inhibition of histone deacetylase 6 (HDAC6) is predicted to deliver both direct antitumor activity and modulation of the antitumor immune response. This study describes the development of a novel HDAC6 inhibitor.

Patients And Methods: KA2507 was characterized in HDAC biochemical and cellular target engagement assays and in preclinical efficacy models of melanoma and colorectal cancer. In a phase I study, KA2507 was administered orally using a 3+3 dose-escalation design (NCT03008018).

Results: KA2507 is a potent and selective inhibitor of HDAC6 (biochemical IC = 2.5 nmol/L). Preclinical models demonstrated antitumor efficacy in syngeneic tumor-bearing mice, with translational studies highlighting modulation of the antitumor immune response. Twenty patients were treated in a phase I study. KA2507 was well tolerated; dose-limiting toxicity was not observed up to the maximum dose administered. Pharmacokinetic profiling supported twice-daily oral dosing. Pharmacodynamic analysis demonstrated selective HDAC6 target engagement in peripheral blood cells, free from off-target class I HDAC activity. Stable disease was the best clinical response (7 patients). Three of these patients (adenoid cystic carcinoma, = 2; rectal adenocarcinoma, = 1) had prolonged disease stabilization that lasted for 16.4, 12.6, and 9.0 months, respectively.

Conclusions: KA2507 is a potent and selective inhibitor of HDAC6 showing antitumor efficacy and immune modulatory effects in preclinical models. In a phase I study, KA2507 showed selective target engagement, no significant toxicities, and prolonged disease stabilization in a subset of patients. Further clinical studies of KA2507 are warranted, as a single agent or, preferably, combined with other immuno-oncology drugs.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0238DOI Listing
May 2021

Patient-Reported Out-of-Pocket Costs and Financial Toxicity During Early-Phase Oncology Clinical Trials.

Oncologist 2021 Mar 29. Epub 2021 Mar 29.

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Clinical trials are an important therapeutic option for patients with cancer. Although financial burden in cancer treatment is well documented, the financial burden associated with clinical trials is not well understood.

Patients And Methods: We conducted a survey regarding economic burden and financial toxicity in patients with cancer enrolled in phase I clinical trials for >1 month. Financial toxicity score was assessed using the Comprehensive Score for Financial Toxicity survey. Patients also reported monthly out-of-pocket (OOP) costs.

Results: Two hundred and thirteen patients completed the survey (72% non-Hispanic White; 45% with annual income ≤$60,000; 50% lived >300 miles from the clinic; 37% required air travel). Forty-eight percent of patients had monthly OOP costs of at least $1,000. Fifty-five percent and 64% of patients reported unanticipated medical and nonmedical expenses, respectively. Worse financial toxicity was associated with yearly household income <$60,000 (odds ratio [OR]: 2.7; p = .008), having unanticipated medical costs (OR: 3.2; p = .024), and living >100 miles away from the clinical trial hospital (OR: 2.3; p = .043). Non-White or Hispanic patients (OR: 2.5; p = .011) and patients who were unemployed or not working outside the home (OR: 2.5; p = .016) were more likely to report high unanticipated medical costs.

Conclusion: Among patients with cancer participating in clinical trials, economic burden is high, and most of patients' OOP costs were nonmedical costs. Financial toxicity is disproportionally higher in patients with lower income and those who travel farther, and unexpected medical costs were more common among non-White or Hispanic patients. OOP costs can be substantial and are often unexpected for patients.

Implications For Practice: The financial burden of cancer treatment is well documented, but there are limited data regarding the financial burden associated with cancer clinical trials. This study surveyed 213 patients enrolled in early-phase clinical trials. Monthly out-of-pocket costs were at least $1000 for nearly half of patients. Worse financial toxicity was associated with income <$60,000 and living farther away from the hospital. Racial/ethnic minorities had higher rates of unanticipated medical costs. These data help to quantify the high financial burden for patients and may reveal a cause of disparities in clinical trial enrollment for underrepresented populations.
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http://dx.doi.org/10.1002/onco.13767DOI Listing
March 2021

Overview of Ocular Side Effects of Selinexor.

Oncologist 2021 Mar 16. Epub 2021 Mar 16.

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: The aim of this review is to elucidate the type and frequency of ocular adverse events associated with selinexor with a goal to quantify the occurrence of these events in our investigator-initiated trial.

Methods: We retrospectively reviewed medical records of 174 patients treated with at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents between July 2015 and July 2020 at a comprehensive cancer center in the U.S. All reported ocular adverse events were assessed.

Results: A total of 174 patient medical records were reviewed. All patients received at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents in our cohort of patients with advanced malignancies. A total of 34 (19.54%) patients experienced 37 ocular adverse events. The most frequently reported ocular symptom was blurred vision, which was reported in 22 (12.64%) patients. The most frequently reported treatment-related adverse event was dry eye syndrome reported in 21 (12.1%) patients, and 19 (10.9%) of them were diagnosed with mild dry eye. The second most common treatment-related adverse event was the progression of age-related nuclear sclerosis (cataract) reported in 7 (4.0%) patients. None of the ocular adverse events required therapy discontinuation.

Conclusion: Our findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment-related adverse events were mild dry eye and progression of age-related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation.

Implications For Practice: Patients receiving selinexor in combination with multiple standard chemotherapy or immunotherapy agents were reviewed, with a total of 34 patients experiencing 37 ocular adverse events. Findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment-related adverse events were mild dry eye and progression of age-related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation.
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http://dx.doi.org/10.1002/onco.13756DOI Listing
March 2021

Dose-escalation study of vemurafenib with sorafenib or crizotinib in patients with BRAF-mutated advanced cancers.

Cancer 2021 Feb 29;127(3):391-402. Epub 2020 Oct 29.

Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through the activation of alternative signaling pathways such as RAF/RAS or MET. The authors hypothesized that combining the BRAF inhibitor vemurafenib with either the multikinase inhibitor sorafenib or the MET inhibitor crizotinib could overcome therapeutic resistance.

Methods: Patients with advanced cancers and BRAF mutations were enrolled in a dose-escalation study (3 + 3 design) to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of vemurafenib with sorafenib (VS) or vemurafenib with crizotinib (VC).

Results: In total, 38 patients (VS, n = 24; VC, n = 14) were enrolled, and melanoma was the most represented tumor type (VS, 38%; VC, 64%). In the VS arm, vemurafenib 720 mg twice daily and sorafenib 400 mg am/200 mg pm were identified as the MTDs, DLTs included grade 3 rash (n = 2) and grade 3 hypertension, and partial responses were reported in 5 patients (21%), including 2 with ovarian cancer who had received previous treatment with BRAF, MEK, or ERK inhibitors. In the VC arm, vemurafenib 720 mg twice daily and crizotinib 250 mg daily were identified as the MTDs, DLTs included grade 3 rash (n = 2), and partial responses were reported in 4 patients (29%; melanoma, n = 3; lung adenocarcinoma, n = 1) who had received previous treatment with BRAF, MEK, and/or ERK inhibitors. Optional longitudinal collection of plasma to assess dynamic changes in circulating tumor DNA demonstrated the elimination of BRAF-mutant DNA from plasma during therapy (P = .005).

Conclusions: Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors.
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http://dx.doi.org/10.1002/cncr.33242DOI Listing
February 2021

Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors.

Clin Cancer Res 2021 Mar 28;27(5):1247-1255. Epub 2020 Oct 28.

Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Doublets of everolimus with letrozole or trastuzumab have demonstrated activity against HER2-positive breast cancer, suggesting that the triple combination can have synergistic anticancer activity.

Patients And Methods: This first-in-human dose-escalation study (NCT02152943) enrolled patients with hormone receptor- positive, HER2-positive (defined by amplification, overexpression, or mutation) treatment-refractory advanced cancers to receive escalating doses (3+3 design) of daily oral letrozole (days 1-21), daily oral everolimus (days 1-21), and intravenous trastuzumab (day 1) every 21 days to determine dose-limiting toxicities (DLT) and MTD or recommended phase II dose (RP2D).

Results: A total of 32 patients with hormone receptor-positive, HER2-positive (amplification, = 27; overexpression, = 1; and mutation, = 4) advanced breast cancer ( = 26) or other cancers ( = 6) were enrolled. The most frequent grade ≥3 adverse events included hyperglycemia ( = 4), anemia ( = 3), thrombocytopenia ( = 2), and mucositis ( = 2). DLTs included grade 3 mucositis and grade 4 neutropenia, and trastuzumab given as an 8 mg/kg loading dose on day 1 of cycle 1 followed by a 6 mg/kg maintenance dose on day 1 of subsequent cycles plus 10 mg everolimus daily and 2.5 mg letrozole daily every 21 days was declared as RP2D. Five patients with breast cancer (four with amplification and one with mutation) had partial responses. amplification in circulating cell-free DNA at baseline was associated with shorter progression-free and overall survival durations ( < 0.05).

Conclusions: Everolimus, letrozole, and trastuzumab have a favorable safety profile and elicit encouraging signals of anticancer activity in patients with heavily pretreated hormone receptor- and HER2-positive advanced cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2878DOI Listing
March 2021

Evaluating the psychometric properties of the Immunotherapy module of the MD Anderson Symptom Inventory.

J Immunother Cancer 2020 10;8(2)

Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Introduction: Immunotherapies have revolutionized the treatment of various cancers, but little is known about their symptomatic toxicity. Assessing these symptoms is best accomplished by asking the patients themselves. However, such reports are subjective and may face challenges as bonafide scientific data. Demonstrating the validity of symptom assessment tools, mainly through the reduction of measurement errors, has the potential to improve patient care if these tools are widely adopted. To that end, we present herein the psychometric properties of the Immunotherapy for Early-Phase Trials module of the MD Anderson Symptom Inventory (MDASI-Immunotherapy EPT) in patients receiving various immunotherapies in early phase trials at a major cancer center.

Methods: One hundred forty-five patients completed the inventory at baseline, with 85 of them also doing so after 9 weeks of treatment. The mean (±SD) age of the patients was 57.0±12.9 years. Also, 56% of the patients were women, 79% identified as white, and 49% had at least some college education.

Results: The internal consistency reliability of the MDASI-Immunotherapy EPT was excellent, as the Cronbach's alphas for all of its subscales were at least 0.88 (range 0.88-0.95). Known-group validity based on Eastern Cooperative Oncology Group performance status groupings was excellent at 9 weeks after the start of an immunotherapy trial for the MDASI-Immunotherapy EPT severity (effect size, 0.96) and interference (effect size, 0.82) subscales. We found substantial changes in the symptom items difficulty remembering (effect size, -0.85), fever and/or chills (effect size, -0.63), disturbed sleep (effect size, -0.52), diarrhea (effect size, -0.42), and swelling of hands, legs, or feet (effect size, -0.39).

Conclusions: In conclusion, the MDASI-Immunotherapy EPT is a valid, reliable, and sensitive tool for measuring symptomatic toxicity.
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http://dx.doi.org/10.1136/jitc-2020-000931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590372PMC
October 2020

Innovative trial design in precision oncology.

Semin Cancer Biol 2020 Oct 3. Epub 2020 Oct 3.

Department of Public Health Sciences, 5841 S. Maryland Ave, MC2000, Chicago, IL 60637, United States. Electronic address:

Genomic profiling technologies have enabled the development of targeted therapies designed to target specific biomarkers and molecular pathways involved in the pathophysiology of tumor initiation, metastasis, and drug resistance. In recent years, clinical trials with innovative design focus on the development of novel agents based on specific patient molecular alterations or other tumor characteristics and include patients with heterogenous tumor types. Precision oncology studies with innovative design associated with novel dose-finding approaches and data analysis focusing on subgroups of patients are characteristic of master protocols. Real-world data, patient-reported outcomes, and N-of-1 trials enhance the knowledge base of evidence to deliver personalized treatment to patients. Master protocols accelerate drug development by enabling simultaneous multiple sub-studies that match the patient's tumor molecular profile with experimental treatment arms. However, the increased flexibility of precision oncology trials is often associated with small subpopulations of patients, which may be underpowered to draw statistically robust conclusions. Despite their limitations, innovative clinical trials continue to rapidly translate the emerging discoveries of novel drugs into unprecedented clinical outcomes in patients with cancer and to accelerate the implementation of precision oncology.
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http://dx.doi.org/10.1016/j.semcancer.2020.09.006DOI Listing
October 2020

Transcriptomics and solid tumors: The next frontier in precision cancer medicine.

Semin Cancer Biol 2020 Sep 17. Epub 2020 Sep 17.

Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, CA, USA.

Transcriptomics, which encompasses assessments of alternative splicing and alternative polyadenylation, identification of fusion transcripts, explorations of noncoding RNAs, transcript annotation, and discovery of novel transcripts, is a valuable tool for understanding cancer mechanisms and identifying biomarkers. Recent advances in high-throughput technologies have enabled large-scale gene expression profiling. Importantly, RNA expression profiling of tumor tissue has been successfully used to determine clinically actionable molecular alterations. The WINTHER precision medicine clinical trial was the first prospective trial in diverse solid malignancies that assessed both genomics and transcriptomics to match treatments to specific molecular alterations. The use of transcriptome analysis in WINTHER and other trials increased the number of targetable -omic changes compared to genomic profiling alone. Other applications of transcriptomics involve the evaluation of tumor and circulating noncoding RNAs as predictive and prognostic biomarkers, the improvement of risk stratification by the use of prognostic and predictive multigene assays, the identification of fusion transcripts that drive tumors, and an improved understanding of the impact of DNA changes as some genomic alterations are silenced at the RNA level. Finally, RNA sequencing and gene expression analysis have been incorporated into clinical trials to identify markers predicting response to immunotherapy. Many issues regarding the complexity of the analysis, its reproducibility and variability, and the interpretation of the results still need to be addressed. The integration of transcriptomics with genomics, proteomics, epigenetics, and tumor immune profiling will improve biomarker discovery and our understanding of disease mechanisms and, thereby, accelerate the implementation of precision oncology.
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http://dx.doi.org/10.1016/j.semcancer.2020.09.007DOI Listing
September 2020

Targeting () Amplification Identified by Next-Generation Sequencing in Patients With Advanced or Metastatic Solid Tumors Beyond Conventional Indications.

JCO Precis Oncol 2019 21;3. Epub 2019 Oct 21.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Human epidermal growth factor receptor 2 (HER2) is an effective therapeutic target in breast and gastric and gastroesophageal junction cancers. However, less is known about the prevalence of () amplification and the efficacy of HER2-targeted treatment in other tumors.

Patients And Methods: We assessed amplification status among 5,002 patients with advanced disease (excluding breast cancer) who underwent next-generation sequencing. We evaluated the clinical benefit of HER2-targeted therapy by measuring the time-dependent overall survival (OS) from the genomic testing results, progression-free survival (PFS), and PFS during HER2-targeted therapy (PFS2) compared with PFS during prior therapy (PFS1).

Results: Overall, 122 patients (2.4%) had amplification, including patients with endometrial (5.3%), bladder (5.2%), biliary or gallbladder (4.9%), salivary (4.7%), and colorectal cancer (3.6%). Forty patients (38%) with nongastric, nongastroesophageal junction, or nonesophageal cancers received at least one line of HER2-targeted therapy. Patients receiving HER2-targeted therapy had a median OS of 18.6 months, compared with 10.9 months for patients who did not receive HER2-targeted therapy ( = .070). On multivariable analysis, HER2-targeted therapy was significantly associated with increased OS (hazard ratio, 0.5; 95% CI, 0.27 to 0.93; = .029), regardless of sex, age, or number of prior lines of treatment. The PFS2-to-PFS1 ratio was 1.3 or greater in 21 (57%) of 37 patients who received HER2-targeted therapy not in the first line of systemic treatment, and the median PFS2 and PFS1 times were 24 and 13 weeks, respectively ( < .001).

Conclusion: amplifications using next-generation sequencing can be identified in a variety of tumor types. HER2-targeted therapy may confer clinical benefit in tumor types other than those for which HER2 inhibitors are approved.
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http://dx.doi.org/10.1200/PO.18.00345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446516PMC
October 2019

Clinical and Economic Value of Genetic Sequencing for Personalized Therapy in Non-small-cell Lung Cancer.

Clin Lung Cancer 2020 11 5;21(6):477-481. Epub 2020 Jun 5.

Personalized Medicine Coalition, Washington, DC.

Two recent studies examining the clinical and economic value of next-generation sequencing (NGS)-based diagnostic testing (multi-gene panel examining ≥ 30 genes) for non-small-cell lung cancer therapy compared with single gene ALK, EGFR testing to select therapy demonstrated statistically insignificant improvement in population-level overall survival and only a moderate incremental cost-effectiveness ratio associated with the NGS testing approach. The data, however, revealed a key practice gap: many patients with actionable mutations did not receive targeted therapies. This gap is attributed, in part, to limitations in the availability and interpretation of NGS results, sample processing constraints, limited access to targeted therapies, and lagging awareness of the rapidly evolving field of personalized medicine, all of which result in "clinical inertia," (ie, suboptimal use of targeted therapy against an actionable driver alteration identified by NGS testing). Additional analysis estimated that cost-effectiveness would improve significantly if a higher percentage of patients received testing and if all patients who were eligible for targeted therapies received them. Strategies to address implementation barriers will help to realize the full value of NGS testing in cancer care.
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http://dx.doi.org/10.1016/j.cllc.2020.05.029DOI Listing
November 2020

Dual EGFR blockade with cetuximab and erlotinib combined with anti-VEGF antibody bevacizumab in advanced solid tumors: a phase 1 dose escalation triplet combination trial.

Exp Hematol Oncol 2020 20;9. Epub 2020 Apr 20.

3Sarah Cannon Research Institute at HealthONE, Denver, CO USA.

Background: Angiogenesis and activation of the epidermal growth factor (EGFR) pathway play an essential role in tumor proliferation and metastasis. Targeting angiogenesis or EGFR alone does not yield adequate tumor control in most solid tumors. Overcoming intrinsic and/or acquired resistance may need a doublet or triplet therapy strategy. Herein, we report the safety and feasibility of dual EGFR blockade with EGFR monoclonal antibody and EGFR tyrosine kinase inhibitor combined with anti-VEGF antibody in advanced solid tumors.

Methods: We conducted a phase I study combining erlotinib, cetuximab, and bevacizumab. Patients with advanced or metastatic solid tumors (excluding colorectal and non-small cell lung cancers) were analyzed for safety, toxicity profile, and response. Anti-tumor activity was evaluated per response evaluation criteria in solid tumors (RECIST 1.0).

Results: Thirty-six patients received treatment on a range of dose-levels. The most frequent tumor types enrolled were cervical (n = 10), head and neck squamous cell (n = 10), and follicular thyroid (n = 4) cancers. The most common treatment-related grade ≥ 2 adverse events were rash (56%), hypomagnesemia (17%), pruritus (11%), diarrhea (8%), and tumor-related bleeding (8%). Seventeen of 19 patients (89%) treated at the maximum tolerated dose did not present treatment-related dose-limiting toxicity. Fifteen (63%) of the 24 evaluable patients achieved a disease control (stable disease ≥ 4 months (n = 14) and partial response (n = 1). The median number of prior lines of therapies was 3 (range 1-10).

Conclusions: The triplet combination of erlotinib, cetuximab, and bevacizumab was well tolerated, conferring clinical benefit in heavily pretreated patients. Future studies are warranted with second or third-generation EGFR tyrosine kinase triplet combinations in the EGFR pathway aberrant patients. ClinicalTrials.gov Identifier: NCT00543504. Sponsor(s): National Cancer Institute (NCI), MD Anderson Cancer Center.
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http://dx.doi.org/10.1186/s40164-020-00159-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171918PMC
April 2020

Review of precision cancer medicine: Evolution of the treatment paradigm.

Cancer Treat Rev 2020 Jun 31;86:102019. Epub 2020 Mar 31.

Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, CA, USA.

In recent years, biotechnological breakthroughs have led to identification of complex and unique biologic features associated with carcinogenesis. Tumor and cell-free DNA profiling, immune markers, and proteomic and RNA analyses are used to identify these characteristics for optimization of anticancer therapy in individual patients. Consequently, clinical trials have evolved, shifting from tumor type-centered to gene-directed, histology-agnostic, with innovative adaptive design tailored to biomarker profiling with the goal to improve treatment outcomes. A plethora of precision medicine trials have been conducted. The majority of these trials demonstrated that matched therapy is associated with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To improve the implementation of precision medicine, this approach should be used early in the course of the disease, and patients should have complete tumor profiling and access to effective matched therapy. To overcome the complexity of tumor biology, clinical trials with combinations of gene-targeted therapy with immune-targeted approaches (e.g., checkpoint blockade, personalized vaccines and/or chimeric antigen receptor T-cells), hormonal therapy, chemotherapy and/or novel agents should be considered. These studies should target dynamic changes in tumor biologic abnormalities, eliminating minimal residual disease, and eradicating significant subclones that confer resistance to treatment. Mining and expansion of real-world data, facilitated by the use of advanced computer data processing capabilities, may contribute to validation of information to predict new applications for medicines. In this review, we summarize the clinical trials and discuss challenges and opportunities to accelerate the implementation of precision oncology.
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http://dx.doi.org/10.1016/j.ctrv.2020.102019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272286PMC
June 2020

Phase 2 study of pembrolizumab in patients with advanced rare cancers.

J Immunother Cancer 2020 03;8(1)

Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Patients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers.

Methods: In this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR).

Results: A total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma-pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug.

Conclusions: The favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma-pheochromocytoma supports further evaluation of pembrolizumab in this patient population.

Trial Registration Number: NCT02721732.
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http://dx.doi.org/10.1136/jitc-2019-000347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078933PMC
March 2020

Phase I studies of vorinostat with ixazomib or pazopanib imply a role of antiangiogenesis-based therapy for TP53 mutant malignancies.

Sci Rep 2020 02 20;10(1):3080. Epub 2020 Feb 20.

Departments of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

We performed two phase I trials of the histone deacetylase inhibitor vorinostat combined with either the vascular endothelial growth factor inhibitor pazopanib (NCT01339871) or the proteasome inhibitor ixazomib (NCT02042989) in patients with metastatic TP53 mutant solid tumors. Both trials followed a 3 + 3 dose-escalation design allowing for a dose expansion cohort of up to 14 additional patients with a specific tumor type. Patients had to have a confirmed TP53 mutation to be enrolled in NCT02042989. Among patients enrolled in NCT01339871, TP53 mutation status was determined for those for whom tumor specimens were available. The results of NCT01339871 were reported previously. Common treatment-related adverse events in NCT02042989 included anemia, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea. Compared with patients with metastatic TP53 hotspot mutant solid tumors who were treated with ixazomib and vorinostat (n = 59), those who were treated with pazopanib and vorinostat (n = 11) had a significantly higher rate of clinical benefit, defined as stable disease lasting ≥6 months or an objective response (3.4% vs. 45%; p < 0.001), a significantly longer median progression-free survival duration (1.7 months [95% confidence interval (CI), 1.1-2.3] vs. 3.5 months [95% CI, 1.7-5.2]; p = 0.002), and a longer median overall survival duration (7.3 months [95% CI, 4.8-9.8] vs. 12.7 months [95% CI, 7.1-18.3]; p = 0.24). Our two phase I trials provide preliminary evidence supporting the use of antiangiogenisis-based therapy in patients with metastatic TP53 mutant solid tumors, especially in those with metastatic sarcoma or metastatic colorectal cancer.
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http://dx.doi.org/10.1038/s41598-020-58366-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033174PMC
February 2020

Circulating tumor DNA analysis in the era of precision oncology.

Oncotarget 2020 Jan 14;11(2):188-211. Epub 2020 Jan 14.

Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The spatial and temporal genomic heterogeneity of various tumor types and advances in technology have stimulated the development of circulating tumor DNA (ctDNA) genotyping. ctDNA was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is associated with significant risk, when tumor tissue is insufficient or inaccessible, and/or when repeated assessment of tumor molecular abnormalities is needed to optimize treatment. The role of ctDNA is now well established in the clinical decision in certain alterations and tumors, such as the epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer and the v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer. The role of ctDNA analysis in other tumor types remains to be validated. Evolving data indicate the association of ctDNA level with tumor burden, and the usefulness of ctDNA analysis in assessing minimal residual disease, in understanding mechanisms of resistance to treatment, and in dynamically guiding therapy. ctDNA analysis is increasingly used to select therapy. Carefully designed clinical trials that use ctDNA analysis will increase the rate of patients who receive targeted therapy, will elucidate our understanding of evolution of tumor biology and will accelerate drug development and implementation of precision medicine. In this article we provide a critical overview of clinical trials and evolving data of ctDNA analysis in specific tumors and across tumor types.
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http://dx.doi.org/10.18632/oncotarget.27418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968778PMC
January 2020

Pathogenic mutations and overall survival in 3,084 patients with cancer: the Hellenic Cooperative Oncology Group Precision Medicine Initiative.

Oncotarget 2020 Jan 7;11(1):1-14. Epub 2020 Jan 7.

The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Houston, TX, USA.

We evaluated the association between pathogenic mutations and overall survival (OS) in patients with cancer referred to Hellenic Cooperative Oncology Group-affiliated Departments. Patients referred from 12/1980 to 1/2017 had molecular testing (for research) of archival tumor tissue collected at the time of first diagnosis (non-metastatic, 81%; metastatic, 19%). Tumor-specific gene panels (16-101 genes) were used to identify pathogenic mutations in clinically relevant genes. NGS genotyping was performed at the Laboratory of Molecular Oncology, Aristotle University of Thessaloniki. Annotation of mutations was performed at MD Anderson Cancer Center. We analyzed 3,084 patients (median age, 57 years; men, 22%) with sequencing data. Overall, 1,775 (58% of 3,084) patients had pathogenic mutations. The median follow-up was 7.52 years (95% CI, 7.39-7.61). In patients with non-metastatic tumors, after stratification by tumor type, increasing age, higher grade, and histology other than adenocarcinoma were associated with shorter OS. OS was also shorter in patients with pathogenic (HR=1.36; p<0.001), (HR=1.64; p=0.005), and (HR=1.46; p=0.047) mutations compared to wild-type genes. In multivariate analyses, independent prognostic factors predicting shorter OS were pathogenic mutations in (HR=1.37, p=0.002) and (HR=1.50, p=0.027); increasing age (HR=1.02, p<0.001); and increasing grade (HR=1.46, p<0.001). In patients with metastatic cancer, older age and higher grade were associated with shorter OS and maintained their independent prognostic significance (increasing age, HR=1.03, p<0.001 and higher grade, HR=1.73, p<0.001). Analysis of molecular data reveals prognostic biomarkers, regardless of tissue or organ of origin to improve patient management.
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http://dx.doi.org/10.18632/oncotarget.27338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967777PMC
January 2020

Phase 1 Dose Escalation Study of the Allosteric AKT Inhibitor BAY 1125976 in Advanced Solid Cancer-Lack of Association between Activating AKT Mutation and AKT Inhibition-Derived Efficacy.

Cancers (Basel) 2019 Dec 10;11(12). Epub 2019 Dec 10.

Bayer AG, 13353 Berlin, Germany.

This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring the mutation, was performed at the recommended phase 2 dose (R2D) of 60 mg BID. Dose-limiting toxicities (Grades 3-4) were increased in transaminases, γ-glutamyltransferase (γ-GT), and alkaline phosphatase in four patients in both schedules and stomach pain in one patient. Of the 78 patients enrolled, one patient had a partial response, 30 had stable disease, and 38 had progressive disease. The clinical benefit rate was 27.9% among 43 patients treated at the R2D. mutation status was not associated with tumor response. Genetic analyses revealed additional mutations that could promote tumor cell growth despite the inhibition of AKT1/2. BAY 1125976 was well tolerated and inhibited AKT1/2 signaling but did not lead to radiologic or clinical tumor responses. Thus, the refinement of a selection of biomarkers for AKT inhibitors is needed to improve their monotherapy activity.
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http://dx.doi.org/10.3390/cancers11121987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966663PMC
December 2019

Defining, Identifying, and Understanding "Exceptional Responders" in Oncology Using the Tools of Precision Medicine.

Cancer J 2019 Jul/Aug;25(4):296-299

Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Widely available molecular profiling technology, including next-generation sequencing has changed the landscape of drug development in cancer. An increasing number of clinical trials in early drug development require patient selection based on molecular alterations. Concurrently, efforts to identify molecular alterations in tumors that exhibited exceptional response after systemic treatment with standard or investigational agents have been published or are in progress. These discoveries may ultimately serve as predictive markers or "actionable mutations" for future therapies. To test the feasibility of collecting the archival tissues from proposed exceptional responder patients and successful subsequent molecular profiling, the National Cancer Institute opened a nationwide exceptional responder initiative protocol in 2014. In addition, an increasing number of exceptional responder cases have been identified and published from academia institutions. The Network of Enigmatic Exceptional Responders study uses crowdsourcing to identify exceptional responders and will molecularly profile tumors to discern molecular correlates with exceptional response. In this review, we discuss the potential role of exceptional responder molecular analysis in new biomarker discovery efforts to further advance precision medicine in oncology therapeutics.
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http://dx.doi.org/10.1097/PPO.0000000000000392DOI Listing
July 2020

Physiologically-based pharmacokinetic modelling to predict oprozomib CYP3A drug-drug interaction potential in patients with advanced malignancies.

Br J Clin Pharmacol 2019 03 25;85(3):530-539. Epub 2018 Dec 25.

University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Aims: Oprozomib is an oral, second-generation, irreversible proteasome inhibitor currently in clinical development for haematologic malignancies, including multiple myeloma and other malignancies. Oprozomib is a rare example of a small molecule drug that demonstrates cytochrome P450 (CYP) mRNA suppression. This unusual property elicits uncertainty regarding the optimal approach for predicting its drug-drug interaction (DDI) risk. The current study aims to understand DDI potential during early clinical development of oprozomib.

Methods: To support early development of oprozomib (e.g. inclusion/exclusion criteria, combination study design), we used human hepatocyte data and physiologically-based pharmacokinetic (PBPK) modelling to predict its CYP3A4-mediated DDI potential. Subsequently, a clinical DDI study using midazolam as the substrate was conducted in patients with advanced malignancies.

Results: The clinical DDI study enrolled a total of 21 patients, 18 with advanced solid tumours. No patient discontinued oprozomib due to a treatment-related adverse event. The PBPK model prospectively predicted oprozomib 300 mg would not cause a clinically relevant change in exposure to CYP3A4 substrates (≤30%), which was confirmed by the results of this clinical DDI study.

Conclusions: These results indicate oprozomib has a low potential to inhibit the metabolism of CYP3A4 substrates in humans. The study shows that cultured human hepatocytes are a more reliable system for DDI prediction than human liver microsomes for studying this class of compounds. Developing a PBPK model prior to a clinical DDI study has been valuable in supporting clinical development of oprozomib.
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http://dx.doi.org/10.1111/bcp.13817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379218PMC
March 2019

Phase 1 study of the combination of vemurafenib, carboplatin, and paclitaxel in patients with BRAF-mutated melanoma and other advanced malignancies.

Cancer 2019 02 1;125(3):463-472. Epub 2018 Nov 1.

Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: BRAF inhibitors are effective against selected BRAF -mutated tumors. Preclinical data suggest that BRAF inhibition in conjunction with chemotherapy has increased therapeutic activity.

Methods: Patients with advanced cancers and BRAF mutations were enrolled into a dose-escalation study (3+3 design) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs).

Results: Nineteen patients with advanced cancers and BRAF mutations were enrolled and received vemurafenib (480-720 mg orally twice a day), carboplatin (area under the curve [AUC] 5-6 intravenously every 3 weeks), and paclitaxel (100-135 mg/m intravenously every 3 weeks). The MTD was not reached, and vemurafenib at 720 mg twice a day, carboplatin at AUC 5, and paclitaxel at 135 mg/m were the last safe dose levels. DLTs included a persistent grade 2 creatinine elevation (n = 1), grade 3 transaminitis (n = 1), and grade 4 thrombocytopenia (n = 1). Non-dose-limiting toxicities that were grade 3 or higher and occurred in more than 2 patients included grade 3/4 neutropenia (n = 5), grade 3/4 thrombocytopenia (n = 5), grade 3 fatigue (n = 4), and grade 3 anemia (n = 3). Of the 19 patients, 5 (26%; all with melanoma) had a partial response (PR; n = 4) or complete response (CR; n = 1); these responses were mostly durable and lasted 3.1 to 54.1 months. Of the 13 patients previously treated with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, 4 (31%) had a CR (n = 1) or PR (n = 3). Patients not treated with prior platinum therapy had a higher response rate than those who did (45% vs 0%; P = .045).

Conclusions: The combination of vemurafenib, carboplatin, and paclitaxel is well tolerated and demonstrates encouraging activity, predominantly in patients with advanced melanoma and BRAF mutations, regardless of prior treatment with BRAF and/or MEK inhibitors.
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http://dx.doi.org/10.1002/cncr.31812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340722PMC
February 2019

Trial Reporting in Immuno-Oncology (TRIO): an American society of clinical oncology-society for immunotherapy of cancer statement.

J Immunother Cancer 2018 10 19;6(1):108. Epub 2018 Oct 19.

Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.

Purpose: To develop recommendations for clinical trial reporting that address the unique efficacy, toxicity, and combination and sequencing aspects of immuno-oncology (IO) treatments.

Methods: ASCO and the Society for Immunotherapy of Cancer (SITC) convened a working group that consisted of practicing medical oncologists, immunologists, clinical researchers, biostatisticians, and representatives from industry and government to develop Trial Reporting in Immuno-Oncology (TRIO) recommendations. These recommendations are based on expert consensus, given that existing data to support evidence-based recommendations are limited.

Conclusion: The TRIO recommendations are intended to improve the reporting of IO clinical trials and thus provide more complete evidence on the relative benefits and risks of an IO therapeutic approach. Given the rapid expansion of the number of IO clinical trials and ongoing improvements to the evidence base supporting the use of IO treatments in clinical care, these recommendations will likely need regular revision as the IO field develops.
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http://dx.doi.org/10.1186/s40425-018-0426-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195705PMC
October 2018

Trial Reporting in Immuno-Oncology (TRIO): An American Society of Clinical Oncology-Society for Immunotherapy of Cancer Statement.

J Clin Oncol 2019 01 19;37(1):72-80. Epub 2018 Oct 19.

8 Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.

Purpose: To develop recommendations for clinical trial reporting that address the unique efficacy, toxicity, and combination and sequencing aspects of immuno-oncology (IO) treatments.

Methods: ASCO and the Society for Immunotherapy of Cancer (SITC) convened a working group that consisted of practicing medical oncologists, immunologists, clinical researchers, biostatisticians, and representatives from industry and government to develop Trial Reporting in Immuno-Oncology (TRIO) recommendations. These recommendations are based on expert consensus, given that existing data to support evidence-based recommendations are limited.

Conclusion: The TRIO recommendations are intended to improve the reporting of IO clinical trials and thus provide more complete evidence on the relative benefits and risks of an IO therapeutic approach. Given the rapid expansion of the number of IO clinical trials and ongoing improvements to the evidence base supporting the use of IO treatments in clinical care, these recommendations will likely need regular revision as the IO field develops.
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http://dx.doi.org/10.1200/JCO.18.00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354771PMC
January 2019

Outcome analysis of Phase I trial patients with metastatic and/or mutant non-small cell lung cancer.

Oncotarget 2018 Sep 7;9(70):33258-33270. Epub 2018 Sep 7.

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

and mutations, which are the most common genetic drivers of tumorigenesis, are still considered undruggable targets. Therefore, we analyzed these genetic aberrations in metastatic non-small cell lung cancer (NSCLC) for the development of potential therapeutics. One hundred eighty-five consecutive patients with metastatic NSCLC in a phase 1 trial center were included. Their genomic aberrations, clinical characteristics, survivals, and phase 1 trial therapies were analyzed. About 10%, 18%, 36%, and 36% of the patients had metastatic +/+, +/-,-/+, and -/- NSCLC, respectively. The most common concurrent genetic aberrations beside and/or (>5%) were KIT, epidermal growth factor receptor, PIK3CA, c-MET, BRAF, STK11, ATM, CDKN2A, and APC. +/+ NSCLC did not respond well to the phase 1 trial therapy and was associated with markedly worse progression-free (PFS) and overall (OS) survivals than the other three groups together. hotspot mutations at locations other than codon G12 were associated with considerably worse OS than those at this codon. Gene aberration-matched therapy produced prolonged PFS and so was anti-angiogenesis in patients with mutations. Introduction of the evolutionary action score system of missense mutations enabled us to identify a subgroup of NSCLC patients with low-risk mutant p53 proteins having a median OS duration of 64.5 months after initial diagnosis of metastasis. These data suggested that patients with metastatic dual hotspot-mutant NSCLC had poor clinical outcomes. Further analysis identified remarkably prolonged survival in patients with low-risk mutant p53 proteins, which warrants confirmatory studies.
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http://dx.doi.org/10.18632/oncotarget.25947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161801PMC
September 2018

Prevalence of MDM2 amplification and coalterations in 523 advanced cancer patients in the MD Anderson phase 1 clinic.

Oncotarget 2018 Sep 4;9(69):33232-33243. Epub 2018 Sep 4.

Department of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: is the most commonly mutated gene in cancer and codes for the best studied tumor suppressor, p53. MDM2 is involved in the negative regulation of p53 and itself serves as an oncogene, reported to be overexpressed in several cancer tumor types. In this retrospective study, we assessed the occurrence of amplification among patients with various types of cancers and its association with clinical factors, other genetic aberrations, and response to targeted therapy in a phase I clinical trial setting.

Methods: Samples from patients with advanced solid tumors who had been referred to the MD Anderson phase I clinical trials program between January 2011 and January 2016 were collected and analyzed for amplification using FoundationOne's genomic profiling assay. Patients whose tumors expressed amplification were compared to those with tumors of the same histologic types without amplification.

Results: We tested tumors from 523 patients, of which 23 (4.4%) had amplification. The highest prevalence of amplification was in sarcoma (57%), breast cancer (13%) and bladder cancer (9%). Six patients with liposarcoma were treated on phase I protocol with an MDM2 inhibitor. The most common molecular aberrations co-occurring with amplification was amplification (70%). mutation was also detected in 7 patients (30%).

Conclusion: amplification was most commonly associated with liposarcoma. Concomitant alterations in additional genes such as amplification and mutations, along with variable responses to targeted therapies including MDM2 inhibitors, suggest that further combinational studies are needed to target this population.
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http://dx.doi.org/10.18632/oncotarget.26075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145698PMC
September 2018

Phase I Study of the BRAF Inhibitor Vemurafenib in Combination With the Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With -Mutated Malignancies.

JCO Precis Oncol 2018 13;2. Epub 2018 Sep 13.

, , , , , , , , , , , , and , The University of Texas MD Anderson Cancer Center, Houston, TX; and , Sarah Cannon Research Institute at HealthONE, Denver, CO.

Purpose: Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in -mutated advanced solid tumors.

Patients And Methods: We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily.

Results: Twenty patients with advanced cancers were enrolled. The median adult age was 64 years (range, 17 to 85 years); two pediatric patients were 10 and 13 years old. Patients were heavily pretreated with prior BRAF or MEK inhibitors (n = 11), phase I clinical trial therapy (n = 10), surgery (n = 18), radiation therapy (n = 11), and chemotherapy (n=13). One of the two pediatric patients initially experienced grade 3 rash, but after dermatologic intervention, the patient remains on trial with partial response and no dose reduction at time of analysis. Four dose-limiting toxicities (rash, n = 1; fatigue, n = 3) were observed at dose level 2. Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was the maximum-tolerated dose. Overall, four patients (22%) had a partial response and nine patients (50%) had stable disease as best response. One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles.

Conclusion: The combination of vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily is safe and well tolerated and has activity across histologies, with partial responses noted in advanced non-small-cell lung cancer, melanoma, optic nerve glioma, and xanthroastrocytoma, including patients who previously experienced progression on BRAF and/or MEK inhibitor therapy. Further investigation in a larger cohort of molecularly matched patients is warranted.
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http://dx.doi.org/10.1200/PO.18.00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446411PMC
September 2018

Overview of precision oncology trials: challenges and opportunities.

Expert Rev Clin Pharmacol 2018 Aug 10;11(8):797-804. Epub 2018 Aug 10.

a Department of Investigational Cancer Therapeutics , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.

Introduction: In recent years, the therapeutic management of selected patients with cancer has shifted toward the 'precision medicine' approach based on patient's mechanisms of tumorigenesis, and their baseline characteristics and comorbidities. Complete tumor and cell-free DNA profiling using next-generation sequencing, proteomic and RNA analysis, and immune mechanisms should to be taken into consideration and accurate bioinformatic analysis is essential to optimize patient's treatment. Areas covered: The challenges and opportunities of conducting clinical trials in precision oncology are summarized. Expert commentary: Precision medicine has significantly changed the diagnostic and therapeutic landscape of cancer. Successful implementation of precision medicine requires translational and bioinformatics infrastructure to support optimization of treatment selection. Targeted therapy, immunotherapy, T-cell therapy alone or in combination with cytotoxic or other effective therapeutic strategies and innovative clinical trials with adaptive design should be offered to all patients. Data sharing and 'N-of-1' models hold the promise to optimize the treatment of individual patients and expedite drug approval for rare alterations and tumor types. Artificial intelligence will facilitate accurate utilization of sequencing data to perform algorithm analysis. Collaboration of healthcare providers with pharmaceutical and biotechnical companies, scientific organizations, and governmental regulatory agencies have a crucial role in curing cancer.
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http://dx.doi.org/10.1080/17512433.2018.1504677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330881PMC
August 2018

Older adults in phase I clinical trials: a comparative analysis of participation and clinical benefit rate among older adults versus middle age and AYA patients on phase I clinical trials with VEGF/VEGFR inhibitors.

Oncotarget 2018 Jun 22;9(48):28842-28848. Epub 2018 Jun 22.

Department of Investigational Cancer Therapeutics (Phase I Program), University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Older adults aged 65 years and above remain underrepresented in cancer clinical trials. We hypothesized that older participation in early phase trials with VEGF/VEGFR (VEGF/R) inhibitors was lower than cancer prevalence in this group and lower than other age groups (middle age, adolescent/young adults [AYA]).

Results: Of 1489 patients, 278 were older adults (18%, median age 68.9y), 220 AYA (15%, median age 32.6 y), 991 middle age (67%, median age 53.8 y). Common malignancies included gastrointestinal ( = 438, 29%), gynecologic ( = 234, 16%), and thoracic/head/neck ( = 216, 15%). Median time to treatment failure did not vary significantly between the 3 age-based cohorts (3m in older adults, 3.5 m middle age, 3.3 m AYA). OR of achieving clinical benefit in older adults vs middle age (OR 1.10, p 0.19 [two-tailed], p 0.09 [one-tailed]) and AYA vs middle age (OR 0.85, p 0.31 [proportions -test, two tailed], p 0.15 [one-tailed]) showed no significant differences.

Conclusions: Older adults accounted for <20% of participants on phase I clinical trials with VEGF/R inhibitors but those who participated were just as likely to achieve a clinical benefit as AYA and middle age patients. These findings merit further exploration into patient selection for early phase trials.

Methods: We identified and separated patients treated on VEGF/R-inhibitor-based phase I trials from 12/1/2004-07/31/2013 into 3 age-based cohorts, AYA (15-39y), middle age (40-64 y), older adults (65 y+). We analyzed clinical/treatment characteristics and response outcomes, calculating the odds ratios (OR) of clinical benefit (defined as SD ≥ 6months, PR, CR) for older adults and AYAs versus middle age participants.
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http://dx.doi.org/10.18632/oncotarget.25571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034739PMC
June 2018

A nonparametric Bayesian basket trial design.

Biom J 2019 09 28;61(5):1160-1174. Epub 2018 May 28.

Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77005, USA.

Targeted therapies on the basis of genomic aberrations analysis of the tumor have shown promising results in cancer prognosis and treatment. Regardless of tumor type, trials that match patients to targeted therapies for their particular genomic aberrations have become a mainstream direction of therapeutic management of patients with cancer. Therefore, finding the subpopulation of patients who can most benefit from an aberration-specific targeted therapy across multiple cancer types is important. We propose an adaptive Bayesian clinical trial design for patient allocation and subpopulation identification. We start with a decision theoretic approach, including a utility function and a probability model across all possible subpopulation models. The main features of the proposed design and population finding methods are the use of a flexible nonparametric Bayesian survival regression based on a random covariate-dependent partition of patients, and decisions based on a flexible utility function that reflects the requirement of the clinicians appropriately and realistically, and the adaptive allocation of patients to their superior treatments. Through extensive simulation studies, the new method is demonstrated to achieve desirable operating characteristics and compares favorably against the alternatives.
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http://dx.doi.org/10.1002/bimj.201700162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261711PMC
September 2019

Autoimmune Granulomatous Inflammation of Lacrimal Glands and Axonal Neuritis Following Treatment With Ipilimumab and Radiation Therapy.

J Immunother 2018 09;41(7):336-339

Departments of Investigational Cancer Therapeutics.

Immune checkpoint inhibitors such as anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), anti PD-1 (programmed cell death protein 1) and PD-L1 (programmed cell death protein-ligand 1) monoclonal antibodies are emerging as standard oncology treatments in various tumor types. The indications will expand as immunotherapies are being investigated in various tumors with promising results. Currently, there is inadequate identification of predictive biomarkers of response or toxicity. Unique response patterns include pseudoprogression and delayed response. The use of immune checkpoint inhibitors exhibit an unique toxicity profile, the immune-related adverse events (irAEs). The most notable immune reactions are noted in skin (rash), gastrointestinal track (colitis, hepatitis, pancreatitis), lung (pneumonitis), heart (myocarditis), and endocrine system (thyroiditis, hypophysitis). We present a patient with metastatic adenoid cystic carcinoma of the left submandibular gland with granulomatous inflammation of the lacrimal glands and axonal neuritis of the cervical and paraspinal nerves following treatment with ipilimumab and radiation therapy.
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http://dx.doi.org/10.1097/CJI.0000000000000224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086752PMC
September 2018