Phase I Master Protocol of Novel Combination Therapy for Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma

NCT ID: NCT04161248

Last Updated: 2025-05-13

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-02
• Study Completion Date: 2026-07-31

Brief Summary

The purpose of this study is to find the highest dose of a new drug, in combination with standard drugs, which can be tolerated without causing very severe side effects. The study treatment is new agents in combination with R-GDP or an equivalent regimen.

Detailed Description

To find the highest dose of a new drug that can be tolerated without causing severe side effects when receiving R-GDP or an equivalent regimen. This is done by starting at a dose lower than the one that is tolerated in patients when given on its own. Participants are given the new drug together with R-GDP and are watched very closely to see what side effects they have and to make sure the side effects are not severe. If the side effects are not severe, then new participants will be given a higher dose of the new drug. Participants joining the study later on will get higher doses of the new drug than participants who join earlier. This will continue until a dose is found that causes severe but temporary side effects. Doses higher than that will not be given.

Conditions

Lymphoma, B-Cell

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Venetoclax + R-GDP

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Dose Level -1: Venetoclax 200 mg/day days 4-8 cycle 1, days 1-5 cycle 2 and 3, + R-GDP

Dose Level 1: Venetoclax 200 mg/day days 4-10 cycle 1, days 1-10 cycle 2 and 3, + R-GDP

Dose Level 2: Venetoclax 400 mg/day days 4-10 cycle 1, days 1-10 cycle 2 and 3, + R-GDP

Dose Level 3: Venetoclax 800 mg/day days 4-10 cycle 1, days 1-10 cycle 2 and 3, + R-GDP

Rituximab Injection

Intervention Type: DRUG

375 mg/m2 - Day 1, cycle 1.

Rituximab SC

Intervention Type: DRUG

1400 mg fixed dose - Day 1, cycle 2 and 3

Gemcitabine

Intervention Type: DRUG

1000 mg/m2 - Day 1 to day 8

Dexamethasone

Intervention Type: DRUG

40 mg daily - Day 1 to day 4

Cisplatin

Intervention Type: DRUG

75mg/m2 - Day 1

Glofitamab + R-GDP

Group Type: EXPERIMENTAL

Rituximab Injection

Intervention Type: DRUG

375 mg/m2 - Day 1, cycle 1.

Rituximab SC

Intervention Type: DRUG

1400 mg fixed dose - Day 1, cycle 2 and 3

Gemcitabine

Intervention Type: DRUG

1000 mg/m2 - Day 1 to day 8

Dexamethasone

Intervention Type: DRUG

40 mg daily - Day 1 to day 4

Cisplatin

Intervention Type: DRUG

75mg/m2 - Day 1

Glofitamab

Intervention Type: DRUG

Cycle 1: Glofitamab 2.5 mg (day 8) and 10 mg (day 15) + R-GDP Cycle 2: Glofitamab 30 mg (day 8) + R-GDP Cycle 3: Glofitamab 30 mg (day 8) + R-GDP

Tafasitamab + R-GDP

Group Type: EXPERIMENTAL

Tafasitamab

Intervention Type: DRUG

Cycle 1: Tafasitamab (12 mg/kg IV day -1, 8, 15) Cycles 2 and 3: Tafasitamab (12 mg/kg IV day 1, 8, 15)

Interventions

Venetoclax

Dose Level -1: Venetoclax 200 mg/day days 4-8 cycle 1, days 1-5 cycle 2 and 3, + R-GDP

Dose Level 1: Venetoclax 200 mg/day days 4-10 cycle 1, days 1-10 cycle 2 and 3, + R-GDP

Dose Level 2: Venetoclax 400 mg/day days 4-10 cycle 1, days 1-10 cycle 2 and 3, + R-GDP

Dose Level 3: Venetoclax 800 mg/day days 4-10 cycle 1, days 1-10 cycle 2 and 3, + R-GDP

Intervention Type: DRUG

Rituximab Injection

375 mg/m2 - Day 1, cycle 1.

Intervention Type: DRUG

Rituximab SC

1400 mg fixed dose - Day 1, cycle 2 and 3

Intervention Type: DRUG

Gemcitabine

1000 mg/m2 - Day 1 to day 8

Intervention Type: DRUG

Dexamethasone

40 mg daily - Day 1 to day 4

Intervention Type: DRUG

Cisplatin

75mg/m2 - Day 1

Intervention Type: DRUG

Glofitamab

Cycle 1: Glofitamab 2.5 mg (day 8) and 10 mg (day 15) + R-GDP Cycle 2: Glofitamab 30 mg (day 8) + R-GDP Cycle 3: Glofitamab 30 mg (day 8) + R-GDP

Intervention Type: DRUG

Tafasitamab

Cycle 1: Tafasitamab (12 mg/kg IV day -1, 8, 15) Cycles 2 and 3: Tafasitamab (12 mg/kg IV day 1, 8, 15)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients with histologic diagnosis for one of the following histologies according to the World Health Organization: documented at initial diagnosis or at relapse:

• Diffuse large cell lymphoma, B-cell (includes primary mediastinal B-cell lymphoma, T-cell rich B-cell lymphoma);
• Previous indolent lymphoma (follicular lymphoma, marginal zone lymphoma, including extranodal MALT lymphoma, lymphoplasmacytoid lymphoma) with transformation to diffuse large B-cell lymphoma at most recent relapse (biopsy proof of transformation is mandatory).
• Patients with de novo aggressive B-cell lymphoma must have relapsed or progressed, or have biopsy-proven refractory disease, after one prior line of therapy (R-CHOP chemotherapy or equivalent). R-CHOP chemotherapy equivalents include R-CEOP, dose-adjusted EPOCH-R, CODOX-M/IVAC-R, and other combination regimens including a CD20 monoclonal antibody, alkylating agent and anthracycline.
• Patients with histological transformation from low grade lymphoma may have had up to 3 prior treatment regimens. Patients with transformed low grade lymphoma treated with a non-anthracycline regimen may be enrolled at investigator discretion.
• Patient must be considered fit for intensive chemotherapy and ASCT, and an appropriate candidate to receive second-line salvage chemotherapy and ASCT. Individuals older than 65 years of age are not recommended for this study.
• Clinically and / or radiologically measurable disease (1 site dimensionally measurable). Measurements / evaluations must be done within 28 days prior to enrollment using the RECIL and Lugano criteria.
• Age ≥ 16 years. (Note that the lower age limit at each centre will be determined by that centre's policy regarding the age at which an individual may sign his or her own consent.)
• ECOG performance status 0, 1, 2 or 3.
• Life expectancy of ≥ 90 days (3 months).
• Laboratory Requirements: (must be done within 14 days of enrollment)

• Absolute Neutrophil ≥ 1.0 x 10^9/L (independent of growth factor support)
• Platelets ≥ 100 x 10^9/L (50 x 10^9/L if bone marrow involvement by lymphoma, independent of transfusion support)
• AST and ALT ≤ 3x ULN
• Serum total bilirubin≤ 1.5x ULN (≤ 5x ULN if Gilberts Disease)
• Serum Creatinine ≤ 1.5x ULN (or estimated GFR of ≥ 45 mL/min/1.73 m2 using Cockcroft Gault formula)
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate.
• Patients must be accessible for treatment and follow up. Patients enrolled on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 1 ½ hours driving distance) placed on patients being considered for this trial.
• In accordance with CCTG policy, protocol treatment is to begin within 5 working days of patient enrollment.
• Women of childbearing potential who are sexually active must have agreed to use a highly effective contraceptive method during treatment and for 12 months after the end of treatment. Men must not father a baby or donate sperm while taking study treatment, and for 24 months after the last dose.

Exclusion Criteria

• Patients concurrently receiving any other anti-cancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) except for medications that are prescribed for supportive care but may potentially have an anti-cancer effect.

• Systemic therapy (cytotoxics, targeted agents and investigational drugs): patients must have recovered from all reversible toxicity related to prior treatment and have adequate washout prior to enrollment with the longest of:
• Five half-lifes
• Two weeks
• Standard cycle length of prior regimen

• Biologic agents e.g. monoclonal antibodies: not permitted within 28 days prior to enrollment.
• Steroids: avoidance of steroids with anti-neoplastic intent in 7 days prior to study drug is preferred. However, if clinically required, it can be administered at investigator discretion (prednisone 40 mg for 4 days maximum, or equivalent) and must be captured on the electronic case report form.
• Radiation: not permitted within 28 days prior to enrollment.
• Active and uncontrolled central nervous system involvement, meningeal or parenchymal. Patients with CNS disease at initial presentation, and who are in a CNS CR at the time of relapse, are eligible. MRI scanning and / or lumbar puncture should be performed if there is clinical suspicion of active CNS disease.
• Known history of human immunodeficiency virus (HIV), active Hepatitis C virus infection, active Hepatitis B virus infection or any uncontrolled active systemic infection. Patients with Hepatitis B serology suggestive of infection are eligible if they are HBV DNA negative and concurrently treated with anti-viral therapy. Patients with a history of hepatitis C who have eradicated the virus are eligible.
• Patients who have been vaccinated with live, attenuated vaccines within 4 weeks of enrollment.
• Patients with clinically significant pre-existing cardiac conditions, including uncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias, or symptomatic congestive heart failure.
• Patients with known left ventricular ejection fraction (LVEF) < 40%.
• Patients with stroke (including TIA) or acute myocardial infarction within three months prior to enrollment.
• Patients with acute gastrointestinal bleeding within one month prior to enrollment.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. However, patients on active anticancer therapy for other advanced or metastatic malignancies are not eligible, as this is a phase I study identifying a RP2D of a single agent and there is the potential for drug-drug interactions. Consult CCTG for patients who are on adjuvant therapies after curative surgery or in instances where it is felt the patient may be eligible (for example, TCC bladder receiving local therapies or CLL not requiring active therapy).
• Pregnant or lactating females, or women of childbearing potential not willing to use an adequate method of birth control for the duration of the study.
• Patients are not eligible if they have a known hypersensitivity to the study drugs or their components.
• Patients with any other clinically significant medical condition which, in the opinion of the treating physician, makes it undesirable for the patient to participate in the study or which could jeopardize compliance with study requirements including, but not limited to: ongoing or active infection, significant uncontrolled hypertension, or severe psychiatric illness/social situations.

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Roche Pharma AG

INDUSTRY

Sponsor Role: collaborator

AbbVie

INDUSTRY

Sponsor Role: collaborator

Incyte Corporation

INDUSTRY

Sponsor Role: collaborator

Canadian Cancer Trials Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sarit Assouline

Role: STUDY_CHAIR

The Jewish General Hospital, Montreal QC, Canada

Diego Villa

Role: STUDY_CHAIR

BCCA - Vancouver Cancer Centre, BC, Canada

Tara Baetz

Role: STUDY_CHAIR

Cancer Centre of Southeastern Ontario at Kingston, ON, Canada

Locations

BCCA - Vancouver

Vancouver, British Columbia, Canada

Site Status: RECRUITING

Kingston Health Sciences Centre

Kingston, Ontario, Canada

Site Status: RECRUITING

University Health Network

Toronto, Ontario, Canada

Site Status: RECRUITING

The Jewish General Hospital

Montreal, Quebec, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Annette Hay

Role: CONTACT

ahay@ctg.queensu.ca

613-533-6430

Lois Shepherd

Role: CONTACT

lshepherd@ctg.queensu.ca

613-533-6430

Facility Contacts

Diego Villa Restrepo

Role: primary

604 877-6000 ext. 2740

Jill Dudebout

Role: primary

613 533-2946

Anca Prica

Role: primary

416 946-4501 ext. 2249

Sarit Assouline

Role: primary

514 340-8207

Other Identifiers

ML40080

Identifier Type: OTHER

Identifier Source: secondary_id

A17-190

Identifier Type: OTHER

Identifier Source: secondary_id

I-00208-20-06

Identifier Type: OTHER

Identifier Source: secondary_id

LY18

Identifier Type: -

Identifier Source: org_study_id