Phase 1 study of pomalidomide and dexamethasone for relapsed/refractory primary CNS or vitreoretinal lymphoma

Abstract

The combination of pomalidomide (POM) and dexamethasone (DEX) was evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) to determine the maximal tolerated dose (MTD) of POM as the primary objective, and overall response rate (ORR), progression-free survival (PFS), and safety profile as secondary objectives. A cohorts-of-3 study design was used with a dose-escalation schedule consisting of POM (3, 5, 7, or 10 mg) orally daily for 21 days every 28 days and DEX 40 mg orally every week. After 2 cycles, POM was continued alone until disease progression, intolerance, or subject withdrawal. Following MTD determination, the MTD cohort was expanded. Twenty-five of 29 patients with the median of 3 prior treatments were eligible for assessment as per international PCNSL collaborative group criteria. The MTD of POM was 5 mg daily for 21 days every 28 days. Whole-study ORR was 48% (12 of 25; 95% confidence interval [CI], 27.8%, 68.7%) with 6 complete response (CR), 2 complete response, unconfirmed (CRu), and 4 partial response (PR). MTD cohort ORR was 50% (8 of 16; 95% CI, 24.7%, 75.4%) with 5 CR, 1 CRu, and 2 PR. Median PFS was 5.3 months (whole study) and 9 months (for responders). One patient had pseudoprogression. Grade 3/4 hematologic toxicities included neutropenia (21%), anemia (8%), and thrombocytopenia (8%). Grade 3/4 nonhematologic toxicities included lung infection (12%), sepsis (4%), fatigue (8%), syncope (4%), dyspnea (4%), hypoxia (4%), respiratory failure (8%), and rash (4%). POM/DEX treatment is feasible with significant therapeutic activity against relapsed/refractory PCNSL and PVRL. This trial was registered at www.clinicaltrials.gov as #NCT01722305.

Conflict of interest statement

Conflict-of-interest disclosure: L.M.D. has consulting/advisory roles with Roche and Sapience Therapeutics. K.A.J. has consulting/advisory roles with Bristol-Myers Squibb and holds stock in Entegrion Inc. A.M.P.O. has consulting/advisory roles with Bristol-Myers Squibb, Merck, Inovio, Stemline Therapeutics, and Novocure. D.S. has consulting/advisory roles with Genentech. C.G. received research funding from Pharmacyclics. C.B.R. received research funding from Celgene, Novartis, and Millennium (Takeda). H.W.T. received research funding from Celgene, Mundipharma, Bristol-Myers Squibb, TG Therapeutics, and Seattle Genetics. T.E.W. received research funding from Celgene. J.P. has a leadership role in, and holds stock in, LAgen Labs (iPSC derived RPE for laboratory use only). The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Response to study treatment. (A) Response table showing response parameters for the whole study and the MTD dose level (median follow-up, 14.2 months). (B) PFS for all patients. (C) PFS for the subset of patients that experienced a CR, CRu, or PR. CR, complete response; CRu, unconfirmed complete response; NE, not estimable; PR, partial response.

Figure 2.

Swimmer’s plot showing clinical course, outcome events, and number of treatment cycles of each patient in the clinical trial. PD, progressive disease.

Figure 3.

MRI of brain showing CR of relapsed PCNSL to the study treatment. This patient with relapsed PCNSL (A) achieved CR after cycle 8 (B). He achieved PR after cycle 4. This case corresponds to patient 21 in Figure 2.

Figure 4.

Pseudoprogression in a PCNSL patient treated with pomalidomide. (A-B) The patient had stable disease after cycle 2 and (C) showed radiologic findings suggestive of progression of disease on restaging MRI of brain after cycle 4 without clinical deterioration. She was taken off study as per protocol. (D) Repeat MRI of brain 1 month later without any steroid or any other treatment showed radiologic improvement. This case is the patient 11 on Figure 2.