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

• Sponsor: Columbia University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02867618
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arm: 1
• Actual Duration (Months): 44.5
• Patients Per Site Per Month: 0.3

Study Details

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
• 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: Oct 16, 2016
• Actual Primary Completion Date: Jun 30, 2020
• Actual Study Completion Date: Jun 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 Names: 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 Names: (formerly) RP-5264

Outcome Measures

Primary Outcome Measures

1. 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.

2. Objective Response Rate (ORR) (Phase 2) [9 months]

   Defined as best response (complete response and partial response) by 4 cycles.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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)

• Study Protocol and Statistical Analysis Plan - Apr 25, 2018

More Information

Publications

None provided.

• Responsible Party: Columbia University
• ClinicalTrials.gov Identifier: NCT02867618
• Other Study ID Numbers: AAAP5661
• First Posted: Aug 16, 2016
• Last Update Posted: Jul 16, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• 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

Study Results

Participant Flow

Pre-assignment Detail	3 out of 14 subjects were enrolled (consented) but not accrued into study and did not receive study treatment.

Arm/Group Title	Carfilzomib + TGR-1202
Arm/Group Description	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
Period Title: Overall Study
STARTED	11
COMPLETED	11
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Carfilzomib + TGR-1202
Arm/Group Description	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
Overall Participants	14
Age, Customized (participants) [Number]
18-21 years	0 0%
22-29 years	1 7.1%
30-39 years	1 7.1%
40-49 years	0 0%
50-59 years	1 7.1%
60-69 years	2 14.3%
70-79 years	9 64.3%
80-89 years	0 0%
Sex: Female, Male (Count of Participants)
Female	6 42.9%
Male	8 57.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 14.3%
Not Hispanic or Latino	11 78.6%
Unknown or Not Reported	1 7.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 14.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 21.4%
White	8 57.1%
More than one race	0 0%
Unknown or Not Reported	1 7.1%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) (Phase 1) - TGR-1202 Only
Description	The highest dose of the study treatment that does not cause unacceptable side effects.
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

PI left the institution, study data was not complete or analyzed for Carfilzomib (Phase 2).

Arm/Group Title	Carfilzomib + TGR-1202
Arm/Group Description	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
Measure Participants	11
Number [mg]	800

2. Primary Outcome

Title	Objective Response Rate (ORR) (Phase 2)
Description	Defined as best response (complete response and partial response) by 4 cycles.
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

The data was not collected or analyzed due to PI leaving the institution.

Arm/Group Title	Carfilzomib + TGR-1202
Arm/Group Description	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
Measure Participants	0

Adverse Events

Time Frame	Up to 1 year post study treatment
Arm/Group Title	Carfilzomib + TGR-1202
Arm/Group Description	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
All Cause Mortality
	Carfilzomib + TGR-1202
	Affected / at Risk (%)	# Events
Total	1/11 (9.1%)
Serious Adverse Events
	Carfilzomib + TGR-1202
	Affected / at Risk (%)	# Events
Total	1/11 (9.1%)
Blood and lymphatic system disorders
Neutropenia	1/11 (9.1%)	1
Other (Not Including Serious) Adverse Events
	Carfilzomib + TGR-1202
	Affected / at Risk (%)	# Events
Total	0/11 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.