Description:
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.
Title
- Brief Title: Carfilzomib and TGR-1202 in Treatment of R/R Lymphoma
- Official Title: Phase I/II Study of Carfilzomib and a PI3Kdelta Inhibitor TGR-1202 in the Treatment of Patients With Relapsed or Refractory Lymphoma
Clinical Trial IDs
- ORG STUDY ID:
AAAP5661
- NCT ID:
NCT02867618
Conditions
- Hodgkin Disease
- Lymphoma, Non-hodgkin
Interventions
| Drug | Synonyms | Arms |
|---|
| Carfilzomib | Kyprolis | Carfilzomib + TGR-1202 |
| TGR-1202 | (formerly) RP-5264 | Carfilzomib + TGR-1202 |
Purpose
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
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Carfilzomib + TGR-1202 | Experimental | 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. | |
Eligibility 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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Maximum Tolerated Dose (MTD) (Phase 1) - TGR-1202 Only |
| Time Frame: | 9 months |
| Safety Issue: | |
| Description: | The highest dose of the study treatment that does not cause unacceptable side effects. |
Details
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Terminated |
| Lead Sponsor: | Columbia University |
Last Updated
July 16, 2021
