476P Open-label phase I/II study evaluating the tolerability and antitumor activity of selinexor (SEL) and pembrolizumab (pembro) in colorectal cancer (CRC)

e13085 Background: PDM08 is a new active compound with antitumor activity in different cancer models. It is a synthetic derivative of the pyroglutamic acid. The lack of direct effect on tumour cells and antitumor activity in immunodeficient models indicates an immune response mediated mechanism. Toxicology and pharmacology preclinical studies showed a favourable safety profile, confirmed by a single-dose placebo controlled healthy volunteer phase I trial. Methods: A single institution open label phase I study was designed (NCT01380249). PDM08 was administered twice a week for four-week cycles. Initially an accelerate escalation phase was chosen with cohorts of 2 patients who after completing the safety period (2 weeks after last dose) had the possibility of escalate to the next dose level if no grade ≥ 2 toxicity and no progressive disease was observed. After 4 cohorts without meaningful toxicity, this design was amended to open new dose levels after a two-week period of treatment completed by the last patient of the cohort if no grade ≥ 2 toxicity was found. The trial was approved by the Ethics Committee and the Spanish Drug Agency. Extensive pharmacokinetic (PK) and pharmacodynamic (PD) data including serum cytokines, lymphoid subpopulations and immunoglobulins are collected. Preliminary efficacy was evaluated by PET-CT. Results: Since July 2011, 10 patients (pts) were recruited into 6 different dose levels (2pts were escalated) ranged from 0.560 mg to 14 mg. Pt characteristics were: female-male ratio 1:1. Median age: 67 (47-76). ECOG 0: 6 pts. 8 pts had colorectal cancer, 1 lung adenocarcinoma and 1 ovarian carcinoma. Median of previous treatments was 3 ranged 2 to 5. 3 pts presented G1 headache. No Dose Limiting Toxicities were found. Preliminary outcome data showed: best response stable disease for 4 patients, 2 of them being stable for 12 weeks. After 40 target lesions evaluated by PET-CT 6 (15%) showed a reduction in the maximum Standard Uptake Value (SUV) of 18-FDG. Conclusions: PDM08 is the first compound of a new class of drugs that can be dose-escalated safely in an accelerated manner and has promising activity. Last patient will be included in March 2012 so final data for toxicity, PK, PD and efficacy will be provided at the meeting.

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Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

Journal of Clinical Oncology ◽

10.1200/jco.2018.78.9602 ◽

2018 ◽

Vol 36 (32) ◽

pp. 3223-3230 ◽

Cited By ~ 82

Author(s):

Tara C. Mitchell ◽

Omid Hamid ◽

David C. Smith ◽

Todd M. Bauer ◽

Jeffrey S. Wasser ◽

...

Keyword(s):

Antitumor Activity ◽

Phase I ◽

Cell Carcinoma ◽

Solid Tumors ◽

Enzyme Inhibitor ◽

Endometrial Adenocarcinoma ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Open Label ◽

Open Label Phase

Purpose Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported. Patients and Methods Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks. Results Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in ≥ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies. Conclusion Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

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