Carfilzomib and TGR-1202 in Treatment of R/R Lymphoma

• ClinicalTrials.gov Identifier: NCT02867618
• Recruitment Status: Terminated
• First Posted: August 16, 2016
• Results First Posted: July 16, 2021
• Last Update Posted: July 16, 2021
• Sponsor: Columbia University
• Information provided by (Responsible Party): Columbia University

Study Description

Brief Summary:

This is an open label, phase I/II, dose-escalation study in the initial phase I followed by a phase II.

The primary objective of the phase I is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of TGR-1202 and carfilzomib in participants with relapsed and refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). The safety and toxicity of this combination will be evaluated throughout the entire study.

If the combination of TGR-1202 and carfilzomib is found to be feasible and an MTD is established, the phase II part of the study will be initiated.

Phase II will consist of a 2-stage design of the combination of TGR-1202 and carfilzomib for participants with R/R NHL.

Condition or disease	Intervention/treatment	Phase
Hodgkin Disease; Lymphoma, Non-hodgkin	Drug: Carfilzomib; Drug: TGR-1202	Phase 1; Phase 2

Detailed Description:

Dysregulated c-Myc is associated with resistance to chemotherapy and poor survival in aggressive lymphomas. Novel strategies that target this biology could markedly improve the outcome of these participants. To date no drugs that directly target Myc have been approved for cancer treatment. Recent results by Deng et al. (Blood. 2017 Jan 5. PMID: 27784673) described a highly synergistic regimen discovered in preclinical models, through combining TGR-1202, an investigational drug that inhibits PI3K delta, and carfilzomib, a drug approved by the FDA for multiple myeloma. Importantly, the combination of TGR-1202 and carfilzomib acts by potently silencing the translation of c-Myc and inducing apoptosis in many cell lines and primary lymphoma cells representing broad histological subtypes of lymphoma. These results suggest that TGR-1202 and carfilzomib may be highly effective in relapsed and refractory lymphoma where c-Myc plays a key pathological role.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Carfilzomib and a PI3Kdelta Inhibitor TGR-1202 in the Treatment of Patients With Relapsed or Refractory Lymphoma
• Actual Study Start Date: October 16, 2016
• Actual Primary Completion Date: June 30, 2020
• Actual Study Completion Date: June 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Carfilzomib + TGR-1202; Oral TGR-1202 will be given PO once daily on Days 1-28 and carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle.	Drug: Carfilzomib; Carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. This will be in combination with the oral TGR-1202; Other Name: Kyprolis; Drug: TGR-1202; Oral TGR-1202 will be given PO once daily on Days 1-28 . This will be given in combination with the intravenous Carfilzomib; Other Name: (formerly) RP-5264

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) (Phase 1) - TGR-1202 Only [ Time Frame: 9 months ]
   The highest dose of the study treatment that does not cause unacceptable side effects.
2. Objective Response Rate (ORR) (Phase 2) [ Time Frame: 9 months ]
   Defined as best response (complete response and partial response) by 4 cycles.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Target Population Phase I: Patients with relapsed or refractory NHL and HL Phase II: Patients with relapsed or refractory NHL

Inclusion Criteria:

• Phase I: Patients must have histologically confirmed R/R NHL or HL (defined by World Health Organization (WHO) criteria). Patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are eligible. In addition, patients with NHL other than diffuse large B cell lymphomas (DLBCL) must have received at least 2 prior therapies. Patients with DLBCL and HL will be eligible if there is no available standard therapy.
• Phase II: Patients must have histologically confirmed R/R NHL (as defined by WHO criteria). Patients with NHL other than diffuse large B cell lymphomas (DLBCL) must have received at least 2 prior therapies. Patients with DLBCL will be eligible if there is no available standard therapy.
• Must have received front line chemotherapy. No upper limit for the number of prior therapies
• Evaluable Disease in the Phase I, and measurable disease in the Phase II
• Age > 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status < 2
• Patients must have adequate organ and marrow function
• Adequate Contraception
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

1. Prior Therapy Exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Systemic steroids that have not been stabilized (≥ 5 days) to the equivalent of ≤10 mg/day prednisone prior to the start of the study drugs. No other investigational agents are allowed.
2. History of allergic reactions to TGR-1202 or carfilzomib
3. Uncontrolled inter-current illness
4. Pregnant women
5. Nursing women
6. Current malignancy or history of a prior malignancy
7. Patient known to be Human Immunodeficiency Virus (HIV)-positive
8. Active Hepatitis A, Hepatitis B, or Hepatitis C infection

Contacts and Locations

Locations

United States, New York

Columbia University Irving Medical Center - Center for Lymphoid Malignancies

New York, New York, United States, 10019

Sponsors and Collaborators

Columbia University

Investigators

• Principal Investigator: Changchun Deng, MD; Assistant Professor of Clinical Medicine and Experimental Therapeutics

  Study Documents (Full-Text)

Documents provided by Columbia University:

Study Protocol and Statistical Analysis Plan  [PDF] April 25, 2018

More Information

• Responsible Party: Columbia University
• ClinicalTrials.gov Identifier: NCT02867618
• Other Study ID Numbers: AAAP5661
• First Posted: August 16, 2016
• Results First Posted: July 16, 2021
• Last Update Posted: July 16, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lymphoma; Hodgkin Disease; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases