Hodgkin Disease, Lymphoma, Non-hodgkin
Conditions
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.
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.
Interventions
DRUGCarfilzomib
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
DRUGTGR-1202
Oral TGR-1202 will be given PO once daily on Days 1-28 . This will be given in combination with the intravenous Carfilzomib
Sponsors
Columbia University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) (Phase 1) - TGR-1202 Only | 9 months | The highest dose of the study treatment that does not cause unacceptable side effects. |
| Objective Response Rate (ORR) (Phase 2) | 9 months | Defined as best response (complete response and partial response) by 4 cycles. |
Countries
United States
Participant flow
Pre-assignment details
3 out of 14 subjects were enrolled (consented) but not accrued into study and did not receive study treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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.
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
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 | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Carfilzomib + TGR-1202 |
|---|---|
| Age, Customized 18-21 years | 0 participants |
| Age, Customized 22-29 years | 1 participants |
| Age, Customized 30-39 years | 1 participants |
| Age, Customized 40-49 years | 0 participants |
| Age, Customized 50-59 years | 1 participants |
| Age, Customized 60-69 years | 2 participants |
| Age, Customized 70-79 years | 9 participants |
| Age, Customized 80-89 years | 0 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 11 |
| other Total, other adverse events | 0 / 11 |
| serious Total, serious adverse events | 1 / 11 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) (Phase 1) - TGR-1202 Only
The highest dose of the study treatment that does not cause unacceptable side effects.
Time frame: 9 months
Population: PI left the institution, study data was not complete or analyzed for Carfilzomib (Phase 2).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib + TGR-1202 | Maximum Tolerated Dose (MTD) (Phase 1) - TGR-1202 Only | 800 mg |
Primary
Objective Response Rate (ORR) (Phase 2)
Defined as best response (complete response and partial response) by 4 cycles.
Time frame: 9 months
Population: The data was not collected or analyzed due to PI leaving the institution.