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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase I/II Study of Carfilzomib and a PI3Kdelta Inhibitor TGR-1202 in the Treatment of Patients With Relapsed or Refractory Lymphoma

Conditions
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Hodgkin Disease, Lymphoma, Non-hodgkin

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: TGR-1202


Participation Criteria
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Eligibility Criteria
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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: 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. History of allergic reactions to TGR-1202 or carfilzomib Uncontrolled inter-current illness Pregnant women Nursing women Current malignancy or history of a prior malignancy Patient known to be Human Immunodeficiency Virus (HIV)-positive Active Hepatitis A, Hepatitis B, or Hepatitis C infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib + TGR-1202<br>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<br>* 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<br>* Other names: Kyprolis;Drug: TGR-1202<br>* Oral TGR-1202 will be given PO once daily on Days 1-28 . This will be given in combination with the intravenous Carfilzomib<br>* Other names: (formerly) RP-5264;|

What is the study measuring?
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Primary Outcome Measures

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