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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04161248
Recruitment Status : Recruiting
First Posted : November 13, 2019
Last Update Posted : January 25, 2022
Roche Pharma AG
Information provided by (Responsible Party):
Canadian Cancer Trials Group

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.

Condition or disease Intervention/treatment Phase
Lymphoma, B-Cell Drug: Venetoclax Drug: RiTUXimab Injection Drug: Rituximab SC Drug: Gemcitabine Drug: Dexamethasone Drug: Cisplatin Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Master Protocol of Novel Combination Therapy for Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma
Actual Study Start Date : December 6, 2019
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : July 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Venetoclax + R-GDP Drug: 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

Drug: RiTUXimab Injection
375 mg/m2 - Day 1, cycle 1.

Drug: Rituximab SC
1400 mg fixed dose - Day 1, cycle 2 and 3

Drug: Gemcitabine
1000 mg/m2 - Day 1 to day 8

Drug: Dexamethasone
40 mg daily - Day 1 to day 4

Drug: Cisplatin
75mg/m2 - Day 1

Primary Outcome Measures :
  1. Establish recommended Phase II dose of new combination therapy [ Time Frame: 4 years ]

Secondary Outcome Measures :
  1. Overall response rate using RECIL response criteria [ Time Frame: 4 years ]
  2. Overall response rate using the Lugano response criteria [ Time Frame: 4 years ]
  3. Severity of adverse events using CTCAE [ Time Frame: 4 years ]
  4. Stem cell collection rate [ Time Frame: 4 years ]
  5. Transplantation rate [ Time Frame: 4 years ]
  6. Event-free survival [ Time Frame: 4 years ]
  7. Overall Survival [ Time Frame: 4 years ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   16 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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).
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04161248

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Contact: Annette Hay 613-533-6430
Contact: Lois Shepherd 613-533-6430

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Canada, British Columbia
BCCA - Vancouver Cancer Centre Recruiting
Vancouver, British Columbia, Canada, V5Z 4E6
Contact: Diego Villa Restrepo    604 877-6000 ext 2740      
Canada, Ontario
University Health Network Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Anca Prica    416 946-4501 ext 2249      
Canada, Quebec
The Jewish General Hospital Recruiting
Montreal, Quebec, Canada, H3T 1E2
Contact: Sarit Assouline    514 340-8207      
Sponsors and Collaborators
Canadian Cancer Trials Group
Roche Pharma AG
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Study Chair: Sarit Assouline The Jewish General Hospital, Montreal QC, Canada
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Responsible Party: Canadian Cancer Trials Group Identifier: NCT04161248    
Other Study ID Numbers: LY18
ML40080 ( Other Identifier: Roche )
A17-190 ( Other Identifier: Abbvie )
First Posted: November 13, 2019    Key Record Dates
Last Update Posted: January 25, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Lymphoma, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Antineoplastic Agents
Antineoplastic Agents, Immunological
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action