Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies.

BACKGROUND: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4-1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies. METHODS: The primary end point in this six-arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune-related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression-free survival, and overall survival. RESULTS: Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A-C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1-7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression-free survival was 2.1 months (95% CI, 1.8-3.5 months), and overall survival was 9.4 months (95% CI, 5.6-11.9 months). No dose-limiting toxicities or grade 3-5 immune-related adverse events were observed. CONCLUSIONS: The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.

Metastatic extraneural glioblastoma diagnosed with molecular testing.

Glioblastoma, the most common malignant brain tumor in adults, is associated with a median overall survival duration of less than 2 years. Extraneural metastases occur in less than 1% of all patients with glioblastoma. The mechanism of extraneural metastasis is unclear. We present a case of extensive extraneural, extraosseous, epidural, and soft-tissue metastasis of glioblastoma. The diagnosis of metastatic glioblastoma was made only after next-generation sequencing (NGS) of the metastatic paraspinal lesions was completed. The CDK4, pTERT, PTEN, and TP53 molecular alterations seen in the initial intracranial glioblastoma were found in the paraspinal tumor, along with the addition of MYC, which is implicated in angiogenesis and epidermal-to-mesenchymal transition. Immunohistochemical stains showed that neoplastic cells were negative for GFAP. In conclusion, this case raises awareness about the role of NGS in the diagnosis of extraneural glioblastoma. This diagnosis was not possible with histology alone and only became evident after molecular profiling of the metastatic lesions and its comparison to the original tumor.

First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors.

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy. RESULTS: Forty-eight patients were enrolled (dose escalation, n = 40; dose expansion, n = 8). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n = 1) and hypertension (15 mg, n = 2). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n = 7) or stable disease (SD) ≥ 24 weeks (n = 6), including 4/11 (36.4%) with FGFR2 mutations/fusions and cholangiocarcinoma (PR n = 3; SD ≥ 24 weeks n = 1), 3/3 (100.0%) with hormone receptor (HR)-positive/HER2-negative breast cancer (PR n = 2; SD ≥ 24 weeks n = 1), 2/5 (40.0%) with triple-negative breast cancer (TNBC; PR n = 1; SD ≥ 24 weeks n = 1), and 1/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib's half-life was 28-34 hours. CONCLUSIONS: Tinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials.

Innovative trial design in precision oncology.

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.

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

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.

Phase 1b study of combined selinexor and eribulin for the treatment of advanced solid tumors and triple-negative breast cancer.

BACKGROUND: Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination. METHODS: The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort. RESULTS: Patients with TNBC (N = 19), sarcoma (N = 9), and other cancers (N = 3) were enrolled in the dose-escalation cohort (N = 10) and in the dose-expansion cohort (N = 21). The median number lines of prior therapy received was four (range, from one to seven prior lines). The most common treatment-related adverse events for selinexor were nausea (77%), leukopenia (77%), anemia (68%), neutropenia (68%), and fatigue (48%). One dose-limiting toxicity occurred at the first dose level with prolonged grade 3 neutropenia. The recommended phase 2 dose was 80 mg of selinexor orally once per week and 1 mg/m2 eribulin on days 1 and 8 intravenously every 3 weeks. The objective response rate (ORR) was 10% in three patients. In the dose-escalation cohort, the ORR was 10%, whereas six patients with had stable disease. In the TNBC dose-expansion cohort (n = 18), ORR was 11%, and there were two confirmed partial responses with durations of 10.8 and 19.1 months (ongoing). CONCLUSIONS: Selinexor and eribulin had an acceptable toxicity profile and modest overall efficacy with durable responses in select patients. PLAIN LANGUAGE SUMMARY: Effective therapies for advanced, triple-negative breast cancer and sarcoma represent an unmet need. Exportin 1 is associated with the transport of cancer-related proteins. Preclinical studies have demonstrated tumor growth inhibition and enhanced tumor sensitivity in patients who receive selinexor combined with eribulin. In this phase 1b study, the authors evaluated the safety profile and clinical activity of the combination of selinexor, a potent oral inhibitor of exportin 1, and eribulin in patients with advanced cancers enriched for triple-negative breast cancer or sarcoma. The combination was well tolerated; most adverse events were mild or moderate, reversible, and managed with dose modifications or growth factor support. The combination of selinexor and eribulin produced an antitumor response, particularly in some patients with triple-negative breast cancer. This work lays the foundation for prospective investigations of the role of selinexor and eribulin in the treatment of triple-negative breast cancer.

Phase 1 dose-escalation study evaluating the safety, pharmacokinetics, and clinical activity of OBI-3424 in patients with advanced or metastatic solid tumors.

BACKGROUND: Report of a Phase 1 dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264). METHODS: A classic 3 + 3 design was used to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of OBI-3424 administered intravenously, as a single agent, at doses of 1, 2, 4, 6, 8, or 12 mg/m2 (days 1 and 8 of a 21-day cycle, Schedule A) or 8, 10, 12, or 14 mg/m2 (day 1 of a 21-day cycle, Schedule B). RESULTS: Dose-limiting hematologic toxicities at 12 mg/m2 in Schedule A led to dose and schedule modifications (Schedule B). In Schedule B, maximum tolerated dose was not reached at the maximum dose tested (14 mg/m2). Grade ≥3 anemia was noted in 3/6 patients treated at 14 mg/m2; the RP2D was 12 mg/m2 (Schedule B). Grade ≥3 treatment-emergent adverse events were experienced by 19/39 (49%) and included anemia (41%) and thrombocytopenia (26%); three patients experienced serious treatment-emergent adverse events (grade ≥3 anemia and thrombocytopenia). One patient had a partial response and 21/33 (64%) had stable disease. CONCLUSIONS: The RP2D is 12 mg/m2 once every 3 weeks. OBI-3424 was well tolerated; dose-dependent, noncumulative thrombocytopenia and anemia were dose-limiting.

A Phase I Trial of Bevacizumab and Temsirolimus in Combination With Valproic Acid in Advanced Solid Tumors.

BACKGROUND: Preclinical models suggest synergy between anti-angiogenesis therapy, mammalian target of rapamycin (mTOR), and histone deacetylase inhibitors to promote anticancer activity. METHODS: This phase I study enrolled 47 patients between April 2012 and 2018 and determined safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) when combining bevacizumab, temsirolimus, and valproic acid in patients with advanced cancer. RESULTS: Median age of enrolled patients was 56 years. Patients were heavily pretreated with a median of 4 lines of prior therapy. Forty-five patients (95.7%) experienced one or more treatment-related adverse events (TRAEs). Grade 3 TRAEs were lymphopenia (14.9%), thrombocytopenia (8.5%), and mucositis (6.4%). Grade 4 TRAEs included lymphopenia (2.1%) and CNS cerebrovascular ischemia (2.1%). Six patients developed DLTs across 10 dose levels with grade 3 infection, rash, mucositis, bowel perforation, elevated lipase, and grade 4 cerebrovascular ischemia. The MTD was dose level 9 (bevacizumab 5 mg/kg days 1 and 15 intravenously (IV) plus temsirolimus 25 mg days 1, 8, 15, and 22 IV and valproic acid 5 mg/kg on days 1-7 and 15-21 per orally (PO)). Objective response rate (ORR) was 7.9% with confirmed partial response (PRs) in 3 patients (one each in parotid gland, ovarian, and vaginal cancers). Stable disease (SD) ≥+6 months was seen in 5 patients (13.1%). Clinical benefit state (CBR: PR + SD ≥+6 months) was 21%. CONCLUSION: Combination therapy with bevacizumab, temsirolimus, and valproic acid was feasible, but there were numerous toxicities, which will require careful management for future clinical development (ClinicalTrials.gov Identifier: NCT01552434).

Selinexor in combination with weekly paclitaxel in patients with metastatic solid tumors: Results of an open label, single-center, multi-arm phase 1b study with expansion phase in ovarian cancer.

OBJECTIVE: Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound which blocks Exportin-1 (XPO1). Our objective was to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel. METHODS: This was an open label, single-center, multi-arm phase 1b study utilizing a "3 + 3" design and a "basket-type" expansion in recurrent solid tumors. Selinexor (60 mg or 80 mg twice weekly orally) and weekly paclitaxel (80 mg IV 2 week on, 1 week off) were one of 13 parallel arms. Efficacy was evaluated using RECIST version 1.1. RESULTS: All 35 patients treated were evaluable for toxicity and 31 (88%) were evaluable for response. Patient diagnoses included platinum-resistant/refractory ovarian (n = 28), breast (n = 4), prostate (n = 2), and cervical (n = 1) cancer. Patients had a median of four prior therapies (range 1-10), and 47% had a prior taxane in the recurrent setting. There were no DLTs and 60 mg was chosen as the RP2D due to long-term tolerability. Ninety-seven percent of patients had at least one treatment-emergent adverse event (TEAE), and the most common grade ≥ 3 TEAE were neutropenia (46%), anemia (31%), and nausea (21%). Among 24 evaluable patients with ovarian cancer, response rate was 17%, CBR was 58%, and median PFS was 6.8 months (95% CI 3.7, not reached (NR)). CONCLUSIONS: Oral selinexor in combination with weekly paclitaxel demonstrated promising clinical activity with manageable toxicity. This combination should be considered for further exploration in a randomized study, especially in ovarian malignancies.

Supportive care for the prevention of nausea, vomiting and anorexia in a phase 1B study of selinexor in advanced cancer patients: an exploratory study.

INTRODUCTION: Clinical observations of cancer patients treated with selinexor have reported high incidence of nausea and anorexia. The study objective was to investigate the adoption of prophylactic olanzapine for the prevention of nausea, vomiting and anorexia in cancer patients receiving selinexor and standard chemotherapy. METHODS: We retrospectively reviewed supportive care interventions in patients receiving selinexor and recorded frequency of adverse events (NCI-CTAE). Association between categorical variables were analyzed using Fisher's exact tests; repeated measures analysis was performed to assess weight changes over time. RESULTS: Of 124 evaluable patients, 83 (66.9%) were female, 93 were white (75.0%), and the most common cancer was ovarian (N = 30, 24.2%). One hundred and four patients (83.9%) received olanzapine, of which 93 (89.4%) were prophylactically treated, the majority (86.5%) receiving low 2.5 mg daily dose. Other anti-emetics included ondansetron in 90 patients (72.6%), dexamethasone prescribed in 50 patients (40.3%) and metoclopramide in 49 patients (39.5%), while aprepitant/fosaprepitant (N = 2, 1.6%) were prescribed infrequently. Cancer patients receiving prophylactic olanzapine (N = 93) compared to patients who never received olanzapine (N = 20) had more Grade 1 + anorexia (31.2% vs 20.0%), less nausea (53.8% vs 70.0%), less vomiting (33.3% vs 40.0%), and increased hyperglycemia (29.0% vs 10.0%), but differences were non-statistically significant. In addition, there was minimal weight loss over time in both groups and no statistically significant differences in weight loss between groups. CONCLUSION: Prophylactic olanzapine decreased nausea, vomiting and maintained weight over 3 months but did not prevent anorexia in patients receiving selinexor and chemotherapy. Low dose olanzapine was well tolerated but associated with hyperglycemia.

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

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 ).

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

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.

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

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.

Pembrolizumab in Patients with Advanced Metastatic Germ Cell Tumors.

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.

Overview of Ocular Side Effects of Selinexor.

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.

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

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.

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.

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.

Factors affecting symptom presentation in an early-phase clinical trials clinic patient population.

Increasing numbers of oncology therapies are being approved based on early-phase single-arm studies. Yet, little is known regarding the use of patient-reported outcomes in single-arm oncology trials testing novel therapies. We examined patient-reported symptom severity and symptom interference with activity- (WAW: work, general activity, walking) and mood-(REM: relations with others, enjoyment of life, mood) related functioning, and their association with factors known to influence symptom severity reporting, in early-phase clinical trials clinic patients. Patients completed the validated MD Anderson Symptom Inventory, containing 13 severity items and six interference items, each rated on a 0-10 scale (higher scores = worse symptom severity/interference). Performance status (ECOG-PS) and age were ascertained. Multiple linear regression was performed. In 248 phase I patients (51% female, 90% ECOG 0-1, and 74% ≤65 years), 67% of patients had ≥seven concurrent symptoms of any severity level, and 51% of patients described ≥three concurrent symptoms as moderate-to-severe (severity rating ≥ 5). Composite symptom severity, WAW and REM were worse in patients with ECOG-PS ≥ 2 vs. 0-1, and worse in patients with ECOG-PS = 1 than in patients with ECOG-PS = 0. Compared with patients over 65y, adolescent and young adult (AYA) patients (18y-39y) and patients aged 40y to 65y had worse composite symptom severity. As expected, being employed full-time/retired was associated with better symptom profiles in phaseI patients. The variation of symptom burden by performance status and age suggest that these factors need to be considered in the design of early-phase trials, particularly if patient-reported symptoms are used as primary/secondary/exploratory endpoints.

Phase I study of imalumab (BAX69), a fully human recombinant antioxidized macrophage migration inhibitory factor antibody in advanced solid tumours.

AIM: Preclinical evidence suggests that oxidized macrophage migration inhibitory factor (oxMIF) may be involved in carcinogenesis. This phase 1 study (NCT01765790) assessed the safety, tolerability, pharmacokinetics and antitumour activity of imalumab, an oxMIF inhibitor, in patients with advanced cancer using '3 + 3' dose escalation. METHODS: In Schedule 1, patients with solid tumours received doses from 1 to 50 mg/kg IV every 2 weeks. In Schedule 2, patients with metastatic colorectal adenocarcinoma, non-small-cell lung, or ovarian cancer received weekly doses of 10 or 25 mg/kg IV (1 cycle = 28 days). Treatment continued until disease progression, unacceptable toxicity, dose-limiting toxicity, or withdrawal of consent. RESULTS: Fifty of 68 enrolled patients received imalumab. The most common treatment-related adverse events (TRAEs) included fatigue (10%) and vomiting (6%); four grade 3 serious TRAEs (two patients) occurred. The dose-limiting toxicity was allergic alveolitis (one patient, 50 mg/kg every 2 weeks). The maximum tolerated and biologically active doses were 37.5 mg/kg every 2 weeks and 10 mg/kg weekly, respectively. Of 39 assessed patients, 13 had stable disease (≥4 months in 8 patients). CONCLUSIONS: Imalumab had a maximum tolerated dose of 37.5 mg/kg every 2 weeks in patients with advanced solid tumours, with a biologically active dose of 10 mg/kg weekly. Further investigation will help define the role of oxMIF as a cancer treatment target.

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

BACKGROUND: BRAF inhibitors are effective against selected BRAFV600 -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/m2 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/m2 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 BRAFV600 mutations, regardless of prior treatment with BRAF and/or MEK inhibitors.