Publications by authors named "Filip Janku"

241 Publications

A novel method for liquid-phase extraction of cell-free DNA for detection of circulating tumor DNA.

Sci Rep 2021 Oct 4;11(1):19653. Epub 2021 Oct 4.

Phase Scientific International Ltd, Garden Grove, CA, USA.

Low yields of extracted cell-free DNA (cfDNA) from plasma limit continued development of liquid biopsy in cancer, especially in early-stage cancer diagnostics and cancer screening applications. We investigate a novel liquid-phase-based DNA isolation method that utilizes aqueous two-phase systems to purify and concentrate circulating cfDNA. The PHASIFY MAX and PHASIFY ENRICH kits were compared to a commonly employed solid-phase extraction method on their ability to extract cfDNA from a set of 91 frozen plasma samples from cancer patients. Droplet digital PCR (ddPCR) was used as the downstream diagnostic to detect mutant copies. Compared to the QIAamp Circulating Nucleic Acid (QCNA) kit, the PHASIFY MAX method demonstrated 60% increase in DNA yield and 171% increase in mutant copy recovery, and the PHASIFY ENRICH kit demonstrated a 35% decrease in DNA yield with a 153% increase in mutant copy recovery. A follow-up study with PHASIFY ENRICH resulted in the positive conversion of 9 out of 47 plasma samples previously determined negative with QCNA extraction (all with known positive tissue genotyping). Our results indicate that this novel extraction technique offers higher cfDNA recovery resulting in better sensitivity for detection of cfDNA mutations compared to a commonly used solid-phase extraction method.
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http://dx.doi.org/10.1038/s41598-021-98815-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490367PMC
October 2021

Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: Results of a single-center, multi-arm phase Ib study.

Invest New Drugs 2021 Sep 25. Epub 2021 Sep 25.

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

Background: Carboplatin and paclitaxel (CT) is one of the standard chemotherapy regimens used in various tumor types. Preclinical models have suggested that selinexor, a first-in-class oral potent selective inhibitor of nuclear export Exportin-1, and CT exerts antitumor activity in multiple malignancies.

Methods: This was a single-center, multi-arm phase Ib study utilizing a "basket type" expansion. CT and selinexor was employed as one of the 13 parallel arms. Advanced relapsed/refractory solid tumors following standard therapy or where the addition of selinexor to standard regimens deemed appropriate, were eligible.

Results: Of 13 patients treated, 12 patients were evaluable for response. The most common cancers were breast (n = 4), esophageal (n = 2), ovarian (n = 2) and non-small cell lung cancers (n = 2). All 13 patients had at least one treatment-related adverse events (TRAEs) and the most common were neutropenia (85%), leukopenia (85%), thrombocytopenia (85%), anemia (69%), nausea (54%), vomiting (46%), and fatigue (46%). One patient at 60 mg QW experienced DLT with grade 3 nausea and vomiting lasting 3 days. Unconfirmed partial response (uPR) was observed in 3 patients; one patient each with esophageal, breast, and ovarian cancer. One patient with esophageal adenocarcinoma had confirmed PR, however, was discontinued from the study due to clinical progression. Five patients achieved stable disease (SD). Disease control rate was 8%. Majority of patients (77%), including two patients who had uPR, had prior exposure to carboplatin and/or paclitaxel. Time-to-treatment failure (TTF) ranged from 1 to 153 weeks.

Conclusion: The RP2D of selinexor was 60 mg QW in combination with CT. The combination conferred viable clinical activity with durable objective responses which should further be explored in tumor types for which CT is used as standard of care. Trial information. ClinicalTrials.gov Identifier: NCT02419495. Sponsor(s): Karyopharm Therapeutics. (Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495 ).
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http://dx.doi.org/10.1007/s10637-021-01188-1DOI Listing
September 2021

Ripretinib intrapatient dose escalation after disease progression provides clinically meaningful outcomes in advanced gastrointestinal stromal tumour.

Eur J Cancer 2021 Sep 12;155:236-244. Epub 2021 Aug 12.

Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. Electronic address:

Purpose: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and platelet-derived growth factor receptor α kinase signalling. Ripretinib showed preliminary efficacy in patients with advanced gastrointestinal stromal tumour (GIST) in a phase I study across a range of doses. Results were confirmed in the phase III INVICTUS study, and ripretinib 150 mg once daily (QD) was subsequently approved as a ≥fourth-line therapy. Here, we report the phase I study results of intrapatient dose escalation (IPDE) in patients with GIST treated across second, third and later lines of therapy.

Methods: Patients with advanced GIST who experienced disease progression (PD) at ripretinib 150 mg QD could dose escalate to 150 mg twice daily (BID). Progression-free survival (PFS) 1 was calculated from the date of the first dose of ripretinib 150 mg QD to PD (as per Response Evaluation Criteria in Solid Tumours 1.1); PFS2 was from the date of IPDE (150 mg BID) to PD or death. Treatment-emergent adverse events (TEAEs) were summarised by dosing periods and compared descriptively.

Results: Of 142 patients with GIST receiving ripretinib 150 mg QD, 67 underwent IPDE. IPDE provided benefit across all lines of therapy; the median PFS2 was 5.6, 3.3 and 4.6 months for patients on second-, third- and ≥fourth-line therapy, respectively. A partial metabolic response after IPDE was demonstrated in 13 of 37 patients with available positron emission tomography scans. TEAEs reported at both doses were similar.

Conclusion: Ripretinib IPDE after PD provided continued clinical benefit in advanced GIST across second, third and later lines of therapy with a similar safety profile to that observed with the QD regimen.
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http://dx.doi.org/10.1016/j.ejca.2021.07.010DOI Listing
September 2021

Validation of Prognostic Scores in Patients With Metastatic Urothelial Cancer Enrolling in Phase I Targeted Therapy or Next Generation Immunotherapy Trials.

Clin Genitourin Cancer 2021 Jul 12. Epub 2021 Jul 12.

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Introduction: Enrolling patients with metastatic urothelial carcinoma (mUC) in phase I trials provides an opportunity to identify biological drug activity. Developing prognostic scores may aid in patient selection for phase 1 trials.

Patients And Methods: We analyzed records of patients with mUC who participated in targeted therapy and immunotherapy phase I clinical trials at MD Anderson Cancer Center (MDACC). The Bellmunt and Bajorin scores were calculated as bladder cancer-specific prognostic scores. The Royal Marsden Hospital (RMH) and MDACC scores were calculated as phase I prognostic scores. Hazard ratios (HR) were calculated using the Cox proportional hazard model. The prognostic value of the Bellmunt, Bajorin, RMH, and MDACC scores were assessed using the Likelihood ratio (LR) χ2 test and the c-index.

Results: Between 2015 and 2019, 43 patients were enrolled in phase I trials and 12 were enrolled in >I trial leading to a total of 57 trial participants (TPs). Ninty-seven percent of TPs received prior platinum therapy and 60% received a prior checkpoint inhibitor. Median overall survival (OS) and progression-free survival (PFS) were significantly shorter with increasing Bajorin, RMH, or MDACC scores, but not with increasing Bellmunt score. The RMH (c-index=0.658, LR χ2=11.8, P=.008) and MDACC scores (c-index =0.66, LR χ2=12.76, P=.01) outperformed the Bajorin score (c-index=0.522, LR χ2=1.22, P=.5) and the Bellmunt score (c-index=0.537, LR χ2=0.36, P=.9) in predicting overall survivalover. The Bajorin, RMH, and MDACC scores, but not the Bellmunt score, were also predictive of progression-free survival (PFS)prog. The RMH and MDACC scores again outperformed the Bajorin scoreand the Bellmunt score for predicting PFS.

Conclusion: The RMH and MDACC phase I prognostic scores accurately predicted survival in patients with mUC and outperformed the bladder cancer-specific scores at time of enrollment on phase 1 clinical trials. The RMH and MDACC scores could optimize selection of patients with mUC for phase I clinical trials.
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http://dx.doi.org/10.1016/j.clgc.2021.07.004DOI Listing
July 2021

Signed in Blood: Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening.

Cancers (Basel) 2021 Jul 18;13(14). Epub 2021 Jul 18.

WIN Consortium, San Diego, CA 92093, USA.

With the addition of molecular testing to the oncologist's diagnostic toolbox, patients have benefitted from the successes of gene- and immune-directed therapies. These therapies are often most effective when administered to the subset of malignancies harboring the target identified by molecular testing. An important advance in the application of molecular testing is the liquid biopsy, wherein circulating tumor DNA (ctDNA) is analyzed for point mutations, copy number alterations, and amplifications by polymerase chain reaction (PCR) and/or next-generation sequencing (NGS). The advantages of evaluating ctDNA over tissue DNA include (i) ctDNA requires only a tube of blood, rather than an invasive biopsy, (ii) ctDNA can plausibly reflect DNA shedding from multiple metastatic sites while tissue DNA reflects only the piece of tissue biopsied, and (iii) dynamic changes in ctDNA during therapy can be easily followed with repeat blood draws. Tissue biopsies allow comprehensive assessment of DNA, RNA, and protein expression in the tumor and its microenvironment as well as functional assays; however, tumor tissue acquisition is costly with a risk of complications. Herein, we review the ways in which ctDNA assessment can be leveraged to understand the dynamic changes of molecular landscape in cancers.
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http://dx.doi.org/10.3390/cancers13143600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306582PMC
July 2021

Pembrolizumab in Patients with Refractory Cutaneous Squamous Cell Carcinoma: A Phase II Trial.

Adv Ther 2021 08 9;38(8):4581-4591. Epub 2021 Jul 9.

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

Introduction: Patients with advanced cutaneous squamous cell carcinoma (CSCC) have a poor prognosis. Blocking the PD-1-PD-L1 axis has shown promising activity in this patient population. We assessed the safety and antitumor activity of PD-1 inhibitor pembrolizumab in patients with refractory advanced CSCC.

Methods: This was a prespecified subgroup analysis of patients with advanced CSCC who enrolled in an open-label, phase II clinical trial for pembrolizumab in patients with refractory rare cancers during 2016-2018. Patients received pembrolizumab 200 mg intravenously every 21 days until progressive disease, unacceptable adverse event, or completion of 24 months of treatment. The primary endpoint was nonprogression rate (NPR) at 27 weeks; secondary endpoints included safety, objective response rate (ORR) per irRECIST, clinical benefit rate (CBR), progression-free survival, and overall survival.

Results: Twenty patients with refractory CSCC enrolled; 19 were evaluable for efficacy. Median follow-up time was 44.1 months. The NPR at 27 weeks was 37% (95% CI 0.16-0.62). Three patients had a complete response (CR), three had a partial response, and one had stable disease, for an ORR of 32% and a CBR of 37%; median duration of response was 27.3 months. All three patients with a CR remained free of recurrence at the time of writing. Severe treatment-related adverse events (grade ≥ 3) occurred in 10% of patients (2/20). PD-L1 expression was not correlated with response to pembrolizumab.

Conclusion: A long-term follow-up confirms pembrolizumab's antitumor activity and safety profile in patients with refractory CSCC. Patients with a CR may experience cure.

Trial Registration: ClinicalTrials.gov, NCT02721732, Registered March 29, 2016.
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http://dx.doi.org/10.1007/s12325-021-01807-6DOI Listing
August 2021

Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial.

Clin Cancer Res 2021 Aug 2;27(16):4491-4499. Epub 2021 Jun 2.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.

Patients And Methods: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant (m) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.

Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.

Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing m LGG.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364866PMC
August 2021

A Phase I Trial of the MET/ Inhibitor Crizotinib Combined with the VEGF Inhibitor Pazopanib in Patients with Advanced Solid Malignancies.

Onco Targets Ther 2021 7;14:3037-3049. Epub 2021 May 7.

Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USA.

Background: Crizotinib inhibits ALK, MET and ROS1 tyrosine kinases but the development of resistance to monotherapy is an issue. The anti-angiogenic properties of pazopanib could overcome crizotinib drug resistance. Additionally, the anti-angiogenic properties of crizotinib could augment the clinical efficacy of pazopanib.

Methods: We evaluated the safety and responses in patients with advanced solid tumors treated with crizotinib and pazopanib.

Results: Eighty-two patients (median age 53 years, range 18-78 years) were enrolled. The median number of prior systemic therapies was 3 (range, 0-8). We were able to dose escalate to dose level 8 (crizotinib 250 mg twice daily and pazopanib 800 mg daily) with no MTD identified. Grade 3 or 4 toxicities were seen in 32% of patients with the highest prevalence being fatigue (n=9, 11%), diarrhea (n=6, 7%), vomiting (n=3, 4%), anemia (n=2, 2%) and ALT increased (n=2, 2%). Of the 82 patients, 61 (74%) had measurable disease by RECISTv1.1 and reached first restaging (6 weeks). Partial response (PR) was observed in 6/61 (10%) patients, and stable disease (SD) lasting ≥6 months was observed in 10/61 patients (16%) (total = 16/61 (26%) of patients with SD ≥6 months/PR).

Conclusion: Dose level 6 (crizotinib 200 mg twice daily and pazopanib 600 mg daily) was the most tolerable dosing of the combination and can be used in future studies. We also observed moderate clinical activity in patients with advanced solid tumors that had received numerous prior therapies.
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http://dx.doi.org/10.2147/OTT.S291801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114359PMC
May 2021

Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours.

Br J Cancer 2021 Jul 3;125(1):28-37. Epub 2021 May 3.

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

Background: This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours.

Methods: Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, plus additional dosing schedules.

Results: The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8).

Conclusions: Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity.

Clinical Trial Registration: NCT01351103.
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http://dx.doi.org/10.1038/s41416-021-01389-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257624PMC
July 2021

Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi-arm phase Ib study.

Invest New Drugs 2021 10 28;39(5):1357-1365. Epub 2021 Apr 28.

Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

Background Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a "basket type" expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22-68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2-48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495.
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http://dx.doi.org/10.1007/s10637-021-01119-0DOI Listing
October 2021

First-in-human evaluation of the novel mitochondrial complex I inhibitor ASP4132 for treatment of cancer.

Invest New Drugs 2021 10 8;39(5):1348-1356. Epub 2021 Apr 8.

Ball Pharma Consulting, LLC, Chicago, IL, USA.

Background We assessed the safety, tolerability, and pharmacokinetics of mitochondrial complex 1 inhibitor ASP4132. Methods This phase I dose-escalation/dose-expansion study enrolled patients with treatment refractory advanced solid tumors to assess safety, dose-limiting toxicities (DLTs), efficacy and pharmacokinetic or oral ASP4132. Results Overall, 39 patients received ASP4132. Acceptable tolerability of ASP4132 5 mg in the first patient led to enrollment in the 10-mg dose cohort. After two DLTs at the 10-mg dose, additional patients were enrolled in the 5-mg cohort; a 7.5-mg cohort and two intermittent-dosing cohorts (ASP4132 10 mg for 3 days, then 4 days off; ASP4132 15 mg for 1 day, then 6 days off). ASP4132 5 mg was well tolerated; however, multiple DLTs such as fatigue, mental status changes, dizziness, lactic acidosis, enteritis, and posterior reversible encephalopathy syndrome were observed in higher dose cohorts (7.5-mg and intermittent 10-mg and 15-mg dose cohorts). Stable disease (+ 4 % to + 15 %) was observed in 8/39 (20.5 %) patients. ASP4132 plasma pharmacokinetics were characterized by high variability, with rapid absorption and accumulation from slow elimination. Conclusions ASP4132 showed limited clinical activity, and DLTs prohibited dose escalation. Further research is required to determine if DLTs will limit clinical activity of other mitochondrial complex I inhibitors. Clinical Trial ID (clinicaltrials.gov): NCT02383368, March 9, 2015.
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http://dx.doi.org/10.1007/s10637-021-01112-7DOI Listing
October 2021

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

Oncologist 2021 07 21;26(7):588-596. Epub 2021 Apr 21.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265355PMC
July 2021

Precision medicine: preliminary results from the Initiative for Molecular Profiling and Advanced Cancer Therapy 2 (IMPACT2) study.

NPJ Precis Oncol 2021 Mar 19;5(1):21. Epub 2021 Mar 19.

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

Precision medicine is associated with favorable outcomes in selected patients with cancer. Herein, we report an interim analysis of IMPACT2, an ongoing randomized study evaluating genomic profiling and targeted agents in metastatic cancer. Patients with metastatic cancer underwent tumor genomic profiling (ClinialTrials.gov: NCT02152254), and 69 patients met the criteria for randomization. Tumor board and multidisciplinary review of molecular alterations optimized treatment selection. From 5/2014 to 4/2017, 320 patients (median age, 63 years; men, 47%) had tumor molecular aberrations, and 213 (66.56%) received anticancer therapy. The most frequently mutated genes were TP53 (42%), KRAS (16%), PIK3CA (12%), and CDKN2A (11%). The median OS was 10.9 months (95% CI, 8.8-12.9). OS was shorter in patients with higher tumor mutational burden. Independent factors associated with shorter OS were age ≥60 years, liver metastases, low albumin levels, high LDH levels, and KRAS and TP53 mutations. Outcomes for randomized patients will be reported after completion of the study.
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http://dx.doi.org/10.1038/s41698-021-00159-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979841PMC
March 2021

Associations between the gut microbiome and fatigue in cancer patients.

Sci Rep 2021 Mar 12;11(1):5847. Epub 2021 Mar 12.

Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

Fatigue is the most prevalent symptom of cancer and its treatments. Changes in the intestinal microbiome have been identified in chronic fatigue syndrome and other neuropsychiatric disorders, and cancer patients. However, the association between intestinal microbiome and fatigue in patients with advanced cancers has not been evaluated. Understanding the connection between intestinal microbiome and fatigue will provide interventional and therapeutic opportunities to manipulate the microbiome to improve fatigue and other patients' reported outcomes. In this project, we aimed to identify associations between microbiome composition and fatigue in advanced cancer patients. In this cross-sectional observational study at a tertiary cancer care center, we included 88 patients with advanced, metastatic, unresectable cancers who were in a washout period from chemotherapy. We measured fatigue using the MD Anderson Symptom Inventory-Immunotherapy fatigue score, and used 16srRNA to analyze intestinal microbiome. Using correlation analysis we found that Eubacterium hallii was negatively associated with fatigue severity scores (r = - 0.30, p = 0.005), whereas Cosenzaea was positively associated with fatigue scores (r = 0.33, p = 0.0002). We identified microbial species that exhibit distinct composition between high-fatigued and low-fatigued cancer patients. Further studies are warranted to investigate whether modulating the microbiome reduces cancer patients' fatigue severity and improves their quality of life.
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http://dx.doi.org/10.1038/s41598-021-84783-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954807PMC
March 2021

Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies.

Br J Cancer 2021 04 5;124(9):1533-1539. Epub 2021 Mar 5.

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

Background: Arginine depletion interferes with pyrimidine metabolism and DNA damage-repair pathways, and pairing arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG20) with platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs.

Methods: This single-centre, Phase 1 trial was conducted using a 3 + 3 dose escalation designed to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of ADI-PEG20.

Results: We enrolled 99 patients with metastatic argininosuccinate synthetase 1 (ASS1) deficient malignancies. We observed no dose-limiting toxic effects or treatment-related mortality. Three percent of patients discontinued treatment because of toxicity. After treatment, 5% (5/99) of patients had partial responses, and 41% had stable disease. The median progression-free and overall survival durations were 3.62 and 8.06 months, respectively. Substantial arginine depletion and citrulline escalation persisted in most patients through weeks 24 and 8, respectively. Tumour responses were associated with anti-ADI-PEG20 antibody levels at weeks 8 and 16 (p = 0.031 and p = 0.0357, respectively).

Conclusion: Concurrently administered ADI-PEG20 and cisplatin had an acceptable safety profile and had shown antitumour activity against metastatic ASS1-deficient solid tumours. Further evaluation of this treatment combination is warranted.
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http://dx.doi.org/10.1038/s41416-020-01230-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076217PMC
April 2021

Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors.

Clin Cancer Res 2021 May 23;27(10):2723-2733. Epub 2021 Feb 23.

Pharmaceuticals Division, Bayer HealthCare Pharmaceuticals, Inc., Whippany, New Jersey.

Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.

Patients And Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with m solid tumors.

Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG ( = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG.

Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4256DOI Listing
May 2021

Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial.

Sci Rep 2021 02 11;11(1):3667. Epub 2021 Feb 11.

Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, FC8.2026, Houston, TX, 77030, USA.

Vaginal and vulvar squamous cell carcinoma (SCC) are rare tumors that can be challenging to treat in the recurrent or metastatic setting. We present a case series of patients with vaginal or vulvar SCC who were treated with single-agent pembrolizumab as part of a phase II basket clinical trial to evaluate efficacy and safety. Two cases of recurrent and metastatic vaginal SCC, with multiple prior lines of systemic chemotherapy and radiation, received pembrolizumab. One patient had significant reduction (81%) in target tumor lesions prior to treatment discontinuation at cycle 10 following confirmed progression of disease with new metastatic lesions (stable disease by irRECIST criteria). In contrast, the other patient with vaginal SCC discontinued treatment after cycle 3 due to disease progression. Both patients had PD-L1 positive vaginal tumors and tolerated treatment well. One case of recurrent vulvar SCC with multiple surgical resections and prior progression on systemic carboplatin had a 30% reduction in her target tumor lesions following pembrolizumab treatment with a PD-L1 positive tumor. Treatment was discontinued for grade 3 mucositis after cycle 5. Pembrolizumab may provide some clinical benefit to some patients with vaginal or vulvar SCC and is overall safe to utilize in this population. Future studies are needed to evaluate the efficacy of pembrolizumab in these rare tumor types and to identify predictive biomarkers of response.
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http://dx.doi.org/10.1038/s41598-021-83317-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878854PMC
February 2021

Pembrolizumab in Patients with Advanced Metastatic Germ Cell Tumors.

Oncologist 2021 07 12;26(7):558-e1098. Epub 2021 Feb 12.

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

Lessons Learned: Advanced germ cell tumors are aggressive and associated with poor prognosis. Pembrolizumab was overall well tolerated in 12 heavily pretreated patients. Three patients had radiographic stable disease that lasted for 10.9 months, 5.5 months, and 4.5 months, respectively. Published data of immunotherapeutic agents in patients with advanced germ cell tumors are confirmed. The limited antitumor activity of immunotherapy in germ cell tumors is, at least partially, attributed to tumor biology (low tumor mutational burden; low PD-1 expression) and other poor-risk features. Tumor profiling to understand the mechanisms of resistance to pembrolizumab and innovative clinical trials that may include immunotherapy are warranted.

Background: Advanced germ cell tumors are associated with poor prognosis. We investigated the role of pembrolizumab in patients with advanced germ cell tumors.

Methods: We analyzed a prespecified cohort of an open-label, phase II clinical trial in which patients with advanced germ cell tumors were treated with pembrolizumab (200 mg) intravenously every 21 days. The endpoints of the study were the non-progression rate (NPR) at 27 weeks, safety, and tolerability. An NPR >20% was considered successful and worthy of further pursuit.

Results: From August 2016 to February 2018, 12 patients (10 men, 2 women) were treated (median age, 35 years [range, 22-63 years]; median number of prior systemic therapies, 3.5 [range, 2-7]; median number of metastatic sites, 3 [range, 2-8]). Overall, pembrolizumab was well tolerated. One patient experienced both grade 1 immune-related skin rash and grade 3 immune-related pneumonitis. No patient died from toxicity. Three patients had radiographic stable disease that lasted for 10.9 months, 5.5 months, and 4.5 months, respectively. No objective response was noted. The median progression-free survival was 2.4 months (95% confidence interval [CI], 1.5-4.5 months), and the median overall survival was 10.6 months (95% CI, 4.6-27.1 months). The 27-week NPR was 9.0% (95% CI, 0.23-41.2%).

Conclusion: Overall, pembrolizumab was safe and had limited antitumor activity in these patients. In the advanced, metastatic setting, tumor profiling to understand the mechanisms of resistance to immunotherapy and innovative clinical trials to identify efficacious combination regimens rather than off-label use of pembrolizumab are warranted.
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http://dx.doi.org/10.1002/onco.13682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265349PMC
July 2021

Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study.

J Immunother Cancer 2020 12;8(2)

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

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region. Symptoms can be debilitating due to hormonal excess and survival is poor. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there has been interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated 4 patients with pituitary carcinoma with pembrolizumab as part of a phase II clinical trial. Two patients (patients 1 and 2) with functioning corticotroph pituitary carcinomas (refractory to surgery, radiotherapy and chemotherapy) had partial radiographic (60% and 32% per Immune-Related Response Evaluation Criteria In Solid Tumors, respectively) and hormonal responses. Patient 1's response continues 42 months after initiation of pembrolizumab and his tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with and gene mutations. Patient 2's tumor after exposure to temozolomide was not sampled, but prior somatic mutational testing was negative. One patient with a non-functioning corticotroph tumor (patient 3) had a best response of stable disease for 4 months. One patient with a prolactin-secreting carcinoma (patient 4) had progressive disease. The latter 2 patients' tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. Programmed death-ligand 1 staining was negative in all tumors. We report 2 cases of corticotroph pituitary carcinoma responsive to pembrolizumab after prior exposure to alkylating agents. The role of CPIs in treating patients with pituitary carcinoma, the relationship between tumor subtype and response to immunotherapy and mechanisms of hypermutation in this orphan disease require further study.Trial registration number: NCT02721732.
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http://dx.doi.org/10.1136/jitc-2020-001532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757504PMC
December 2020

Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge" (December 4th-5th, 2019, Naples, Italy).

J Transl Med 2021 01 6;19(1):13. Epub 2021 Jan 6.

Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Over the last few years, numerous clinical trials and real-world experience have provided a large amount of evidence demonstrating the potential for long-term survival with immunotherapy agents across various malignancies, beginning with melanoma and extending to other tumours. The clinical success of immune checkpoint blockade has encouraged increasing development of other immunotherapies. It has been estimated that there are over 3000 immuno-oncology trials ongoing, targeting hundreds of disease and immune pathways. Evolving topics on cancer immunotherapy, including the state of the art of immunotherapy across various malignancies, were the focus of discussions at the Immunotherapy Bridge meeting (4-5 December, 2019, Naples, Italy), and are summarised in this report.
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http://dx.doi.org/10.1186/s12967-020-02627-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789268PMC
January 2021

Hormonal modulation of ESR1 mutant metastasis.

Oncogene 2021 02 15;40(5):997-1011. Epub 2020 Dec 15.

Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.

Estrogen receptor alpha gene (ESR1) mutations occur frequently in ER-positive metastatic breast cancer, and confer clinical resistance to aromatase inhibitors. Expression of the ESR1 Y537S mutation induced an epithelial-mesenchymal transition (EMT) with cells exhibiting enhanced migration and invasion potential in vitro. When small subpopulations of Y537S ESR1 mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases. Y537S mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen (Tam) as well as to estradiol (E) withdrawal. Y537S ESR1 mutant primary tumors metastasized efficiently in the absence of E; however, Tam treatment significantly inhibited metastasis to distant sites. We identified a nine-gene expression signature, which predicted clinical outcomes of ER-positive breast cancer patients, as well as breast cancer metastasis to the lung. Androgen receptor (AR) protein levels were increased in mutant models, and the AR agonist dihydrotestosterone significantly inhibited estrogen-regulated gene expression, EMT, and distant metastasis in vivo, suggesting that AR may play a role in distant metastatic progression of ESR1 mutant tumors.
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http://dx.doi.org/10.1038/s41388-020-01563-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020875PMC
February 2021

Molecular Profiling of Metastatic Bladder Cancer Early-Phase Clinical Trial Participants Predicts Patient Outcomes.

Mol Cancer Res 2021 03 15;19(3):395-402. Epub 2020 Dec 15.

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

Prognosis for patients with metastatic bladder carcinoma (mBC) remains limited and in need of novel therapies. We retrospectively analyzed medical records of 43 patients with platinum-refractory metastatic bladder cancer (mBC) who participated in one or more phase I trials of various investigational therapies. Patients' tumors or circulating tumor DNA were analyzed by next-generation sequencing. The median progression-free survival was 4.2 months, the median overall survival was 9.6 months, and the overall response rate was 17.5%. , and alterations were detected in 66%, 29%, 27%, 24%, and 22% of all patients, respectively. Alterations in were almost mutually exclusive of . More than half (64%) of patients with an alt received an FGFR inhibitor, 67% of which achieved disease control. Among patients with urothelial carcinoma histology, those harboring a alteration had a shorter median progression-free survival (PFS) compared with those whose tumors carry wild-type . The reverse relationship was observed in patients harboring an alteration. IMPLICATIONS: Patients with platinum-refractory mBC derive clinical benefit from participating in early-phase clinical trials and their survival outcomes correlate with the genetic profile of the tumor. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/3/395/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0751DOI Listing
March 2021

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

Cancer 2021 02 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 03 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

Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus in Patients with Relapsed Refractory Hodgkin Lymphoma.

Clin Cancer Res 2020 11 14;26(21):5579-5587. Epub 2020 Oct 14.

Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Preclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma.

Patients And Methods: During the dose-escalation study (ClinicalTrials.gov number: NCT01087554) with the HDAC inhibitor vorinostat and the mTOR inhibitor sirolimus (V+S), a patient with Hodgkin lymphoma refractory to nine prior therapies demonstrated a partial response (PR) lasting for 18.5 months, which promoted additional enrollment of patients with Hodgkin lymphoma as well as exploration of an alternative combination of vorinostat and mTOR inhibitor everolimus (V+E).

Results: A total of 40 patients with refractory Hodgkin lymphoma received V+S ( = 22) or V+E ( = 18). Patients received a median of five prior therapies, including brentuximab ( = 39), autologous stem cell transplantation ( = 26), and allogeneic stem cell transplantation ( = 12). The most frequent grade ≥3 treatment-related adverse event was thrombocytopenia in 55% and 67% of patients treated with V+S and V+E, respectively. Complete response was reported in 6 (27%) patients treated with V+S and 2 (11%) patients treated with V+E, and PR was reported in 6 patients (27%) treated with V+S and 4 (22%) patients treated with V+E (objective response rate of 55% and 33%, respectively). In summary, combined HDAC and mTOR inhibition had encouraging activity in heavily pretreated patients with relapsed/refractory Hodgkin lymphoma and warrants further investigation.

Conclusions: Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed refractory Hodgkin lymphoma and warrants further investigation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1215DOI Listing
November 2020

Intratumoral Injection of -NT Spores in Patients with Treatment-refractory Advanced Solid Tumors.

Clin Cancer Res 2021 01 12;27(1):96-106. Epub 2020 Oct 12.

BioMed Valley Discoveries Inc., Kansas City, Missouri.

Purpose: Intratumorally injected -NT (nontoxic; lacking the alpha toxin), an attenuated strain of , replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation.

Patients And Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of -NT across 6 dose cohorts (1 × 10 to 3 × 10 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose.

Results: Among 24 patients, a single intratumoral injection of -NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 10 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis ( = 2) and grade 4 gas gangrene ( = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture ( = 1), limb abscess ( = 1), soft-tissue infection ( = 1), respiratory insufficiency ( = 1), and rash ( = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. -NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses.

Conclusions: Single intratumoral injection of NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of NT in humans.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2065DOI Listing
January 2021

Identification of Actionable Genomic Alterations Using Circulating Cell-Free DNA.

JCO Precis Oncol 2019 24;3. Epub 2019 Sep 24.

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

Purpose: Cell-free DNA (cfDNA) next-generation sequencing is a noninvasive approach for genomic testing. We report the frequency of identifying alterations and their clinical actionability in patients with advanced/metastatic cancer.

Patients And Methods: Prospectively consented patients had cfDNA testing performed. Alterations were assessed for therapeutic implications.

Results: We enrolled 575 patients with 37 tumor types. Of these patients, 438 (76.2%) had at least one alteration detected, and 205 (35.7%) had one or more alterations of high potential for clinical action. In diseases with 10 or more patients enrolled, 50% or more had at least one alteration deemed of high potential for clinical action. Trials were identified in 80% of patients (286 of 357) with any alteration and in 92% of patients (188 of 205) with one or more alterations of high potential for clinical action of whom 57.6% (118 of 205) had 6 or more months of follow-up available. Of these patients, 10% (12 of 118) had received genomically matched therapy through enrollment in clinical trials (n = 8), off-label drug use (n = 3), or standard of care (n = 1). Although 88.6% of all patients had a performance status of 0 or 1 upon enrollment, the primary reason for not acting on alterations was poor performance status at next treatment change (28.1%; 27 of 96).

Conclusion: cfDNA testing represents a readily accessible method for genomic testing and allows for detection of genomic alterations in most patients with advanced disease. Utility may be higher in patients interested in investigational therapeutics with adequate performance status. Additional study is needed to determine whether utility is enhanced by testing earlier in the treatment course.
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http://dx.doi.org/10.1200/PO.19.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448805PMC
September 2019

Dual inhibition of BRAF and mTOR in -mutant pediatric, adolescent, and young adult brain tumors.

Cold Spring Harb Mol Case Stud 2020 08 25;6(4). Epub 2020 Aug 25.

Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Although BRAF inhibition has demonstrated activity in -mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with -mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.
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http://dx.doi.org/10.1101/mcs.a005041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476413PMC
August 2020

Switch Control Inhibition of KIT and PDGFRA in Patients With Advanced Gastrointestinal Stromal Tumor: A Phase I Study of Ripretinib.

J Clin Oncol 2020 10 17;38(28):3294-3303. Epub 2020 Aug 17.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Purpose: In advanced gastrointestinal stromal tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of and mutations.

Patients And Methods: This first-in-human, to our knowledge, phase I study of ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a dose-escalation phase and subsequent expansion phase at the recommended phase II dose (RP2D). Eligible patients included those with advanced GIST, intolerant to or experienced progression on ≥ 1 line of systemic therapy, and other advanced malignancies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and preliminary antitumor activity were evaluated.

Results: At data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were enrolled, with 68 patients in the dose-escalation phase. Three DLTs were reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was established as the RP2D. The most frequent (> 30%) treatment-emergent adverse events in patients with GIST receiving ripretinib 150 mg once daily (n = 142) were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69 [48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62 [43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]), and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n = 16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31; second line) and median progression-free survival ranging from 5.5 months (fourth line or greater) to 10.7 months (second line), on the basis of investigator assessment, were observed.

Conclusion: Ripretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA mutant kinases with promising activity in patients with refractory advanced GIST.
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http://dx.doi.org/10.1200/JCO.20.00522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526717PMC
October 2020
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