IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab in patients with advanced cancer.

BACKGROUND: Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin-paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer. METHODS: IOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin-paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination. RESULTS: A total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin-paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin-paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A-D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A-D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A-D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%. CONCLUSIONS: Dostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens. TRIAL REGISTRATION NUMBER: NCT03307785.

Author Correction: Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer.

Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.

Open-label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer.

IMPORTANCE: Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC). OBJECTIVE: To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC. DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019. INTERVENTIONS: Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival. RESULTS: Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected. CONCLUSIONS AND RELEVANCE: Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02657889.

Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma.

IMPORTANCE: Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. OBJECTIVE: To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. DESIGN, SETTING, AND PARTICIPANTS: The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. INTERVENTIONS: The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. RESULTS: Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. CONCLUSIONS AND RELEVANCE: Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02657889.

Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors.

Purpose This phase Ib study (NCT01862328) evaluated the maximum tolerated dose (MTD), safety, and efficacy of pevonedistat in combination with standard-of-care chemotherapies in patients with solid tumors. Methods Patients received pevonedistat with docetaxel (arm 1, n = 22), carboplatin plus paclitaxel (arm 2, n = 26), or gemcitabine (arm 3, n = 10) in 21-days (arms 1 and 2) or 28-days (arm 3) cycles. A lead-in cohort (arm 2a, n = 6) determined the arm 2 carboplatin dose. Dose escalation proceeded via continual modified reassessment. Results Pevonedistat MTD was 25 mg/m2 (arm 1) or 20 mg/m2 (arm 2); arm 3 was discontinued due to poor tolerability. Fifteen (23%) patients experienced dose-limiting toxicities during cycle 1 (grade ≥3 liver enzyme elevations, febrile neutropenia, and thrombocytopenia), managed with dose holds or reductions. Drug-related adverse events (AEs) occurred in 95% of patients. Most common AEs included fatigue (56%) and nausea (50%). One drug-related death occurred in arm 3 (febrile neutropenia). Pevonedistat exposure increased when co-administered with carboplatin plus paclitaxel; no obvious changes were observed when co-administered with docetaxel or gemcitabine. Among 54 response-evaluable patients, two had complete responses (arm 2) and 10 had partial responses (three in arm 1, one in arm 2a, six in arm 2); overall response rates were 16% (arm 1) and 35% (arm 2). High ERCC1 expression correlated with clinical benefit in arm 2. Conclusion Pevonedistat with docetaxel or with carboplatin plus paclitaxel was tolerable without cumulative toxicity. Sustained clinical responses were observed in pretreated patients receiving pevonedistat with carboplatin and paclitaxel. ClinicalTrials.gov identifier: NCT01862328.

Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML.

Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.

An Evaluation of Treatment Patterns and Outcomes in Elderly Patients Newly Diagnosed With Acute Myeloid Leukemia: A Retrospective Analysis of Electronic Medical Records From US Community Oncology Practices.

BACKGROUND: Many elderly patients with acute myeloid leukemia (AML) are considered ineligible for standard intensive induction therapy due to performance status and comorbidities. We analyzed treatment patterns and outcomes among elderly patients newly diagnosed with AML in the US community oncology setting. METHODS: A retrospective observational study was conducted using patient-level data from a network of US community oncology practices provided by Altos Solutions. Patients aged ≥ 60 years, diagnosed with AML between November 2005 and February 2014, with ≥ 1 recorded visit and ≥ 6 months between diagnosis and data cutoff, were included. Only patients who received active treatment or best supportive care (BSC) per National Comprehensive Cancer Network (NCCN) AML Guidelines were analyzed. RESULTS: Of 1139 patients meeting the inclusion criteria, 922 (median age 76 years) received NCCN-recommended treatments: standard induction (n = 5), low-intensity therapy (n = 425), BSC with hydroxyurea (HU) (n = 36), or BSC without HU (n = 455). For the low-intensity therapy cohort, median time from diagnosis to treatment initiation was 17 days; median duration of therapy was 5.1 months. Median overall survival (OS) from diagnosis in the low-intensity, BSC with HU, and BSC without HU groups was 12.3, 7.0, and 49.4 months, respectively. Median time to next therapy/death was 10.1 months in patients receiving low-intensity therapy. A higher proportion of patients receiving low-intensity therapy required transfusion or other supportive care versus those receiving BSC. CONCLUSIONS: As expected, OS in patients receiving low-intensity therapy or BSC with HU is poor for elderly patients with AML. Remarkably, intensive induction strategies are rarely used for older patients in community oncology practice.

A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma.

Purpose The therapeutic index of proteasome inhibitors may be improved through selective inhibition of a sub-component of the ubiquitin-proteasome system, such as the NEDD8-conjugation pathway. This multicenter, phase I, dose-escalation study assessed safety and the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of pevonedistat, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients with metastatic melanoma. Methods Patients received intravenous pevonedistat on Days 1, 4, 8, 11 (schedule A) or 1, 8, 15 (schedule B) of 21-day cycles. Results 26 patients received pevonedistat 50-278 mg/m(2) on schedule A; 11 patients received pevonedistat 157 mg/m(2) on schedule B. The schedule A MTD was 209 mg/m(2): dose-limiting toxicities (DLTs) included grade 3 hypophosphatemia and grade 3 increased blood creatinine (associated with grade 3 hyperbilirubinemia). Two schedule A patients experienced acute organ failure toxicities, one of whom experienced grade 5 acute renal failure. Dose escalation did not occur in schedule B: DLTs included grade 3 myocarditis, grade 2 acute renal failure, and grade 2 hyperbilirubinemia in a single patient. Pevonedistat pharmacokinetics were approximately dose-proportional across the dose range studied, with a biphasic disposition profile characterized by a short elimination half-life (~10 h). Pharmacodynamic studies showed increases in NAE-regulated transcripts post-treatment; all post-dose biopsy samples were positive for pevonedistat-NEDD8 adduct. One schedule A patient achieved a partial response; 15 patients had stable disease (4 lasting ≥6.5 months). Conclusions Pevonedistat was generally well tolerated at the MTD. Anticipated pharmacodynamic effects of NAE inhibition were observed with single-agent pevonedistat in peripheral blood and tumor tissue.

Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma.

PURPOSE: Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma. EXPERIMENTAL DESIGN: Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m(2) on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m(2) on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles. RESULTS: Maximum tolerated doses were 110 mg/m(2) (schedule A) and 196 mg/m(2) (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade ≥3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease. CONCLUSIONS: Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma.

Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors.

PURPOSE: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies. EXPERIMENTAL DESIGN: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0. RESULTS: Schedule A MTD was 50 mg/m(2); based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m(2), respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥ 3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. CONCLUSIONS: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m(2) and 67 mg/m(2). DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors.

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor ß by the monoclonal antibody fresolimumab (GC1008).

Fresolimumab is an antibody capable of neutralizing all human isoforms of transforming growth factor beta (TGFß) and has demonstrated anticancer activity in investigational studies. Inhibition of TGFß by fresolimumab can potentially result in the development of cutaneous lesions. The aim of this study was to investigate the clinical, histological, and immunohistochemical characteristics of cutaneous neoplasms associated with fresolimumab. Skin biopsies (n = 24) were collected and analyzed from patients (n = 5) with treatment-emergent, cutaneous lesions arising during a phase 1 study of multiple doses of fresolimumab in patients (n = 29) with melanoma or renal cell carcinoma. Blinded, independent histological review and measurements of Ki-67, p53, and HPV integration were performed. Based on central review, four patients developed lesions with histological characteristics of keratoacanthomas, and of these patients, a single case of well-differentiated squamous cell carcinoma was also found. Expression of Ki-67, no evidence of p53 overexpression, and only focal positivity for human papillomavirus RNA by in situ hybridization in 4/18 cases were consistent with these findings. Following completion of fresolimumab, lesions spontaneously resolved. Therefore, benign, reversible keratoacanthomas were the most common cutaneous neoplasms observed, a finding of importance for adverse event monitoring, patient care, and optimization of therapies targeting TGFß.

First-in-human phase I dose escalation study of a second-generation non-ansamycin HSP90 inhibitor, AT13387, in patients with advanced solid tumors.

PURPOSE: AT13387 is a potent second-generation, fragment-derived HSP90 inhibitor. This phase I study investigated the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and safety, pharmacokinetic, and pharmacodynamic profiles of two AT13387 regimens in a refractory solid tumor population. EXPERIMENTAL DESIGN: Standard 3+3 dose escalation was used. MTD and RP2D determinations were based on the occurrence of dose-limiting toxicities (DLT) and overall toxicity, respectively. Pharmacokinetic parameters were measured after single and multiple doses. AT13387-mediated induction of HSP70 was evaluated in plasma, peripheral blood mononuclear cells, and paired tumor biopsies. RESULTS: Sixty-two patients were treated with doses ranging from 10 to 120 mg/m(2) twice weekly and 150 to 310 mg/m(2) once weekly (both for 3 weeks every 28 days). One DLT of visual disturbance occurred at 120 mg/m(2), which was considered the MTD and RP2D for the twice-weekly regimen. No formal DLTs occurred in the once-weekly regimen, but multiple moderately severe toxicities, including diarrhea, nausea, vomiting, fatigue, and systemic infusion reactions, led to selection of 260 mg/m(2) as the RP2D. Exposures of AT13387 increased proportionally with dose. Target engagement as measured by HSP70 induction occurred in plasma and tumor biopsy samples. One patient with gastrointestinal stromal tumor (GIST) who had progressive disease on imatinib had a partial response and remained on treatment for 10 months. Twenty-one patients (34%) had stable disease, which lasted >120 days in 7 patients. CONCLUSION: AT13387 administered once or twice weekly has an acceptable safety profile and demonstrated evidence of target engagement and preliminary antitumor activity.

Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFß) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma.

BACKGROUND: In advanced cancers, transforming growth factor-beta (TGFß) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFß monoclonal antibody that neutralizes all isoforms of TGFß. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. METHODS: In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed. RESULTS: Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4-44.4 weeks). CONCLUSIONS: GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments. TRIAL REGISTRATION: Clinicaltrials.gov NCT00356460.

Phase II trial of imatinib in AIDS-associated Kaposi's sarcoma: AIDS Malignancy Consortium Protocol 042.

PURPOSE: Kaposi's sarcoma (KS) is a disease of multifocal vascular proliferation that requires infection with KS herpes virus (KSHV/HHV-8). Activation of the c-kit and platelet-derived growth factor (PDGF) receptors by autocrine/paracrine mechanisms follows endothelial cell KSHV infection. In a pilot study, imatinib, a c-kit/PDGF-receptor inhibitor, induced partial regression of AIDS-associated KS (AIDS-KS) in five of 10 patients. PATIENTS AND METHODS: This multicenter phase II study was designed to estimate the response rate to imatinib in AIDS-KS. Secondary objectives included investigation of predictors of response and imatinib pharmacokinetics in patients on antiretrovirals. Patients received imatinib 400 mg/day by mouth for up to 12 months with dose escalation up to 600 mg/day at 3 months if their disease was stable. RESULTS: Thirty patients were treated at 12 AIDS Malignancy Consortium sites. Ten patients (33.3%) achieved partial response, six (20%) had stable disease, and seven (23.3%) exhibited KS progression. Nine patients completed 52 weeks of imatinib therapy. The median treatment duration was 22.5 weeks. Only five patients (16.7%) discontinued therapy owing to adverse events. Antiretroviral regimens did not significantly alter imatinib metabolism. Activating mutations in PDGF-R and c-kit were not found at baseline or at disease progression. We found no correlation with response with changes in any of the candidate cytokines. CONCLUSION: Imatinib has activity in AIDS-KS. Pharmacokinetic interactions with antiretroviral drugs did not correlate with toxicity. Thirty percent of patients showed long-term clinical benefit and remained on imatinib for the entire year. These results suggest imatinib is well tolerated and may be an alternative therapy for some patients with AIDS-KS.

A phase 1/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy in human immunodeficiency virus-positive patients with cancer: AIDS Malignancy Consortium trial AMC 061.

BACKGROUND: The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients (ClinicalTrials.gov identifier: NCT00890747). METHODS: In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. RESULTS: Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. CONCLUSIONS: Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir.

Pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone in AIDS-related lymphoma: AIDS Malignancy Consortium Study 047.

PURPOSE: Infusional chemotherapy is efficacious in patients with AIDS-related lymphoma, but it may be difficult to administer. We studied standard agents with rituximab plus pegylated liposomal doxorubicin (DR-COP) in an attempt to provide a more practical approach to therapy while ascertaining rates of response, potential infectious complications, and prognostic role of biologic markers. PATIENTS AND METHODS: We conducted a prospective, multi-institutional phase II trial, employing (day 1) pegylated liposomal doxorubicin 40 mg/m(2), rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2) (not > 2 mg), and prednisone 100 mg orally on days 1 through 5, with concomitant antiretroviral therapy. RESULTS: In 40 evaluable patients, median CD4 cells was 114/µL (range, 5 to 1,026/µL), and median HIV-1 viral load (VL) was 25,000 copies/mL. High or intermediate/high age-adjusted International Prognostic Index was present in 28%. Overall response was 67.5%, with complete remission in 47.5% (95% CI, 31.5 to 63.9). Of 19 complete responders, 84% had extranodal disease, 47% had CD4 < 100/µL, and 47% had VL > 50,000 copies/mL; one relapsed. With 25.5-month median follow-up, 62% (95% CI, 44 to 75) of patients remain alive. Sixteen patients (40%) experienced 22 infections, with grade 4 in only two (5%). No patient died as a result of infection during treatment; one had opportunistic infection. CONCLUSION: Profound immunodeficiency and high HIV-1 viral load do not preclude attainment of complete response after DR-COP with highly active antiretroviral therapy. The regimen is tolerable, and use of rituximab was not associated with death as a result of infection during treatment. This approach may be useful in patients in whom the more intensive infusional regimens are impractical.

Cannabidiol inhibits growth and induces programmed cell death in kaposi sarcoma-associated herpesvirus-infected endothelium.

Kaposi sarcoma is the most common neoplasm caused by Kaposi sarcoma-associated herpesvirus (KSHV). It is prevalent among the elderly in the Mediterranean, inhabitants of sub-Saharan Africa, and immunocompromised individuals such as organ transplant recipients and AIDS patients. Current treatments for Kaposi sarcoma can inhibit tumor growth but are not able to eliminate KSHV from the host. When the host's immune system weakens, KSHV begins to replicate again, and active tumor growth ensues. New therapeutic approaches are needed. Cannabidiol (CBD), a plant-derived cannabinoid, exhibits promising antitumor effects without inducing psychoactive side effects. CBD is emerging as a novel therapeutic for various disorders, including cancer. In this study, we investigated the effects of CBD both on the infection of endothelial cells (ECs) by KSHV and on the growth and apoptosis of KSHV-infected ECs, an in vitro model for the transformation of normal endothelium to Kaposi sarcoma. While CBD did not affect the efficiency with which KSHV infected ECs, it reduced proliferation and induced apoptosis in those infected by the virus. CBD inhibited the expression of KSHV viral G protein-coupled receptor (vGPCR), its agonist, the chemokine growth-regulated protein α (GRO-α), vascular endothelial growth factor receptor 3 (VEGFR-3), and the VEGFR-3 ligand, vascular endothelial growth factor C (VEGF-C). This suggests a potential mechanism by which CBD exerts its effects on KSHV-infected endothelium and supports the further examination of CBD as a novel targeted agent for the treatment of Kaposi sarcoma.