We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle ...arrest or apoptosis in TP53-wild-type (WT) tumors.
Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days.
Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg) and 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg.
ALRN-6924 was well tolerated and demonstrated antitumor activity.
Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).
Patients received ...tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.
One hundred and forty-nine patients received tepotinib (R1:
= 42; R2:
= 45; R3:
= 62). Although six patients reported DLTs one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg), the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.
Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily.
abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.
To report the overall survival (OS) and clinical characteristics of BRAF inhibitor-naive long-term responders and survivors treated with dabrafenib plus trametinib in a phase I and II study of ...patients with BRAF V600 mutation-positive metastatic melanoma.
BRAF inhibitor-naive patients treated with dabrafenib 150 mg twice daily plus trametinib 2 mg daily (the 150/2 group) from the non-randomly assigned (part B) and randomly assigned (part C) cohorts of the study were analyzed for progression-free and OS separately. Baseline characteristics and factors on treatment were analyzed for associations with durable responses and OS.
For BRAF inhibitor-naive patients in the 150/2 groups (n = 78), the progression-free survival at 1, 2, and 3 years was 44%, 22%, and 18%, respectively, for part B (n = 24) and 41%, 25%, and 21%, respectively, for part C (n = 54). Median OS was 27.4 months in part B and 25 months in part C. OS at 1, 2, and 3 years was 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with metastases in fewer than three organ sites and lower baseline lactate dehydrogenase. OS at 3 years was 62% in patients with normal baseline lactate dehydrogenase and 63% in patients with a complete response.
Dabrafenib plus trametinib results in a median OS of more than 2 years in BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma, and approximately 20% were progression free at 3 years. Durable responses occurred in patients with good prognostic features at baseline, which may be predictive.
T cell immunoglobulin and mucin domain containing protein 3 (TIM-3) is a receptor found on a multitude of immune cells and is commonly overexpressed in patients with cancer. Due to its selective ...expression in immune cells and its preliminary efficacy in preclinical models, TIM-3 is a promising target as a treatment for cancer. Both monotherapy and combination regimens are being developed and are currently under investigation. This clinical review seeks to summarize and compile past, present, and future TIM-3 inhibitors in clinical trials.
PIK3CA mutations may predict response to PI3K/AKT/mTOR inhibitors in patients with advanced cancers, but the relevance of mutation subtype has not been investigated. Patients with diverse cancers ...referred to the Clinical Center for Targeted Therapy were analyzed for PIK3CA and, if possible, KRAS mutations. Patients with PIK3CA mutations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway. Overall, 105 (10%) of 1,012 patients tested harbored PIK3CA mutations. Sixty-six (median 3 prior therapies) of the 105 PIK3CA-mutant patients, including 16 individuals (of 55 PIK3CA-mutant patients tested) with simultaneous KRAS mutations, were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor; 17% (11/66) achieved a partial response (PR). Patients with a PIK3CA H1047R mutation compared with patients who had other PIK3CA mutations or patients with wild-type PIK3CA treated on the same protocols had a higher PR rate (6/16, 38% vs. 5/50; 10% vs. 23/174, 13%, respectively; all P ≤ 0.02). None of the 16 patients with coexisting PIK3CA and KRAS mutations in codon 12 or 13 attained a PR (0/16, 0%). Patients treated with combination therapy versus single-agent therapies had a higher PR rate (11/38, 29% vs. 0/28, 0%; P = 0.002). Multivariate analysis showed that H1047R was the only independent factor predicting response OR 6.6, 95% confidence interval (CI), 1.02-43.0, P = 0.047). Our data suggest that interaction between PIK3CA mutation H1047R versus other aberrations and response to PI3K/AKT/mTOR axis inhibitors warrants further exploration.
The purpose of this study was to confirm our previous results that targeted agents matched with tumor molecular alterations were associated with improved outcomes compared with nonmatched therapy in ...patients with advanced cancer.
Outcomes of patients who were referred for treatment on phase I clinical trials at The University of Texas MD Anderson Cancer Center (Houston, TX) from March 2011 to January 2012 were compared between those who had received targeted therapy and those for whom no targeted therapy was available. Two-month landmark analyses for overall and progression-free survival (PFS) combining previously published and validation cohort patient data were performed.
In patients with one alteration, matched therapy (n = 143) compared with treatment without matching (n = 236) was associated with a higher objective response rate (12% vs. 5%; P < 0.0001), longer PFS (median, 3.9 vs. 2.2 months; P = 0.001), and longer survival (median, 11.4 vs. 8.6 months; P = 0.04). In multivariate analysis, matched therapy was an independent factor predicting response (P < 0.015) and PFS (P < 0.004). Two-month landmark analyses in the matched therapy group demonstrated that the median survival of responders was 30.5 months compared with 11.3 months for nonresponders (P = 0.01); and the median PFS was 38.7 months compared with 5.9 months, respectively (P < 0.0001). The respective values in the nonmatched therapy group were 9.8 and 9.4 months (P = 0.46) and 8.5 and 4.2 months (P = 0.18).
This validation analysis confirms our previous observations. In the matched therapy group, 2-month landmark analyses demonstrated that responders have longer survival and PFS than nonresponders.
B7-H3 is a transmembrane receptor highly prevalent on malignant cells and plays an important role in adaptive immunity that is not fully elucidated. Targeted B7-H3 inhibitors, including antibody-drug ...conjugates, radioimmunotherapy, and monoclonal antibodies, are a new class of antineoplastic agents showing promising preliminary clinical efficacy, observed with several of these agents against multiple tumor types. Particularly promising treatments are enoblituzumab for prostate cancer,
I-omburtamab for central nervous system malignancies, and HS-20093 for small-cell lung cancer but further studies are warranted. There are clinical trials on the horizon that have not yet enrolled patients examining chimeric antigen receptor T-cell therapies, bi- and tri-specific killer engagers, and dual-affinity retargeting proteins. These data will be telling of the efficacy of B7-H3 inhibitors in both hematologic and solid malignancies. This study aimed to compile available results of B7-H3 inhibitors in oncology clinical trials.
Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of ...IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.
Background
Microsatellite‐stable (MSS) colorectal cancer (CRC) tends to be poorly immunogenic, with limited treatment options. In MSS CRC xenograft models, trifluridine/tipiracil (FTD/TPI) plus ...programed death 1 inhibitors resulted in synergistic antitumor activity and increased tumor immunogenicity. This phase 2 study evaluated FTD/TPI plus nivolumab in patients with MSS metastatic CRC.
Methods
This single‐arm, safety lead‐in study used a Simon's two‐stage design (enrolling 6 patients in the safety lead‐in, proceeding to stage 2 if ≥2 of the first 15 patients achieved a partial or complete response per immune‐related response criteria irRC within 6 months). Patients with histologically proven MSS mCRC, and disease progression after ≥2 prior chemotherapy regimens received FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 every 28 days) plus nivolumab (3 mg/kg every 2 weeks).
Results
Between August 2016 and January 2017, 18 patients (50% men; median age 56.5 years) were enrolled; 72% had colon cancer and 56% had KRAS mutations. All patients received treatment (median, 2.5 cycles range, 1–8). No dose‐limiting toxicities were observed in the study. The most frequent adverse events (AEs) of any cause and grade were nausea (67%), diarrhea (61%), and neutropenia (50%); 13 patients (72%) experienced grade ≥3 AEs. No patients discontinued treatment because of AEs. No patient achieved a tumor response (either per Response Evaluation Criteria in Solid Tumors RECIST or irRC), and the study did not progress to the second stage. Stable disease was achieved in 8 patients per irRC and in 10 patients per RECIST. Median progression‐free survival was 2.2 months (95% CI, 1.8–6.0 months) per irRC and 2.8 months (95% CI, 1.8–5.1 months) per RECIST.
Conclusion
Patients with refractory MSS metastatic CRC failed to experience clinical benefit with FTD/TPI plus nivolumab, although safety data in this population indicated tolerability and feasibility of this combination.
Trial registration number
NCT02860546.
This phase 2 study utilized a Simon’s 2‐stage design to evaluate the combination of trifluridine/tipiracil (FTD/TPI) and nivolumab in patients with microsatellite‐stable (MSS) metastatic colorectal cancer (mCRC). Among 18 patients enrolled in the first stage, no clinical responses were observed with FTD/TPI plus nivolumab, and therefore, the study did not progress to the second stage. Patients with refractory MSS mCRC failed to experience clinical benefit with the FTD/TPI plus nivolumab combination, although safety data indicated that this combination was tolerable in these patients.
To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or ...metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression.
In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA).
Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens (N = 155), PD-L1 protein expression in tumor and immune cells was negative (<1%) more commonly in adenocarcinoma than in squamous tumors. PD-L1 mRNA levels were lower in adenocarcinoma than squamous cell tumors (1.2 vs 5.0 mean transcripts per million, respectively) in TCGA.
Cemiplimab has activity in cervical squamous cell carcinoma. The phase I results, combined with results from other anti–PD-1 trials in cervical cancer and our biomarker analyses have informed the design of the ongoing phase III trial, with the primary overall survival hierarchical analyses being done first in patients with squamous histology.
•Cemiplimab provided clinical benefit among patients with advanced cervical cancer in a phase I study.•Responding patients had squamous histology.•PD-L1 protein expression in commercially available samples and PD-L1 mRNA expression in The Cancer Genome Atlas were analyzed.•Analyses of PD-L1 protein and mRNA expression showed greater PD-L1 expression in squamous versus non-squamous cervical cancer.•Results support the rationale and design of a global randomized phase III cemiplimab study in metastatic cervical cancer.
PDF
