Novel Combination Therapy in the Treatment of Relapsed and Refractory Aggressive B-Cell Lymphoma
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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. |
| ClinicalTrials.gov Identifier: NCT02436707 |
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Recruitment Status :
Recruiting
First Posted : May 7, 2015
Last Update Posted : May 10, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Lymphoma | Drug: Ibrutinib Drug: Rituximab Drug: Gemcitabine Drug: Dexamethasone Drug: Cisplatin Drug: Mesna Drug: Cyclophosphamide Drug: Etoposide Drug: G-CSF Drug: Selinexor | Phase 2 |
This research is being done to try to find new combinations of treatment that may be better for treating patients with this disease. It is not clear however if these treatments can offer better results than standard treatment.
The study uses a "pick the winner" design to facilitate efficient screening of novel combination treatment regimens and select those meeting pre-specified criteria for testing in the phase III setting. All novel treatment options will be compared against the standard treatment for this disease: rituximab plus gemcitabine, dexemthasone, and cisplatin (R-GDP).
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 320 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Multi-Stage Randomized Phase II Study of Novel Combination Therapy in the Treatment of Relapsed and Refractory Aggressive B-Cell Lymphoma |
| Actual Study Start Date : | May 5, 2015 |
| Estimated Primary Completion Date : | December 31, 2023 |
| Estimated Study Completion Date : | December 31, 2024 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: R-GDP
Rituximab - 375 mg/m2 IV, 1.5 - 6 hours D1 (prior to cisplatin); Gemcitabine - 1000 mg/m2, IV 30 min D1, D8; Dexamethasone - 40 mg daily PO D1 - D4; Cisplatin - 75 mg/m2 IV, 1 hour D1; |
Drug: Rituximab Drug: Gemcitabine Drug: Dexamethasone Drug: Cisplatin |
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Experimental: Ibrutinib plus R-GDP (ACCRUAL COMPLETE)
Ibrutinib 560 mg PO -- D1 - D21 Rituximab 375 mg/m2 IV 1.5 - 6 hours D1 (prior to cisplatin) Gemcitabine 1000 mg/m2 IV 30 min D1, D8 Dexamethasone 40 mg daily PO -- D1 - D4 Cisplatin 75 mg/m2 IV 1 hour D1 |
Drug: Ibrutinib Drug: Rituximab Drug: Gemcitabine Drug: Dexamethasone Drug: Cisplatin |
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Experimental: R-DICEP
Rituximab 375 mg/m2 IV 1.5-6hrs Day 1 and Day 5 prior to Cisplatin Mesna 1.75 g/m2 IV 24 hour Cycle 1, Day 2, Day 3 and Day 4 Cyclophosphamide, 1.75 g/m2 IV 2 hours, Day 2, Day 3 and Day 4 Etoposide 350 mg/m2 IV 2 hours, Day 2, Day 3 and Day 4 Cisplatin 35 mg/m2 IV, 2 hours, Day 2, Day 3 and Day 4 G-CSF 300 mcg (<60kg); 480 mcg (60-90kg); 600 mcg (>90kg); SC, Daily, starting Day 15 until apheresis completed. |
Drug: Rituximab Drug: Cisplatin Drug: Mesna Drug: Cyclophosphamide Drug: Etoposide Drug: G-CSF |
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Experimental: Selinexor + R-GDP
Selinexor - 40mg PO, D1, D3, D8 Rituximab - 375 mg/m2 IV, 1.5 - 6 hours D1 (prior to cisplatin); Gemcitabine - 1000 mg/m2, IV 30 min D1, D8; Dexamethasone - 40 mg daily PO D1 - D4; Cisplatin - 75 mg/m2 IV, 1 hour D1; |
Drug: Rituximab Drug: Gemcitabine Drug: Dexamethasone Drug: Cisplatin Drug: Selinexor |
- Measure overall response rate [ Time Frame: 2 years ]To determine the overall response rate (complete and partial response) to novel combination therapy in patients with relapsed and refractory aggressive B cell lymphoma
- Number and severity of adverse events [ Time Frame: 2 years ]To evaluate the tolerability and toxicity of novel combinations. Adverse events will be monitored on an ongoing basis by the central office and their frequencies reported annually at investigators' meetings. Safety and tolerability will be reviewed in the first six patients assigned to ibrutinib plus R-GDP as part of a safety run-in. Ibrutinib dose will be reduced for subjects subsequently enrolled if necessary
- Transplantation rate [ Time Frame: 2 years ]A non-inferiority analysis of transplantation rate will be conducted with 10% non-inferiority margin. The one-sided 80% asymptotic confidence limit of the difference in transplantation rate will be calculated between treatment and control arms.
- Stem cell collection rate [ Time Frame: 2 years ]Stem cell collection rate defined as collection of ≥ 2 x 106 CD34+ cells/kg.
- Event free Survival Rate [ Time Frame: 2 years ]• Event free survival (EFS) at one year defined as time from study entry to any treatment failure including disease progression, or discontinuation of treatment for any reason
- Overall Survival [ Time Frame: 2 years ]
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.
| Ages Eligible for Study: | 16 Years to 65 Years (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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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);
- Unclassifiable B-cell lymphoma with indeterminate features between diffuse large B-cell lymphoma and Burkitt lymphoma.
- Biopsy proof of disease at initial diagnosis is mandatory. A repeat biopsy in primary refractory disease is preferred but not mandatory to confirm progressive disease. A biopsy at relapse is preferred but not mandatory. Participating centres must designate a local reference expert pathologist who will confirm the diagnosis for the patients enrolled at that centre.
- Patients must be CD20+ in order to be eligible for the study.
- Clinically and/or radiologically measurable disease (one site bidimensionally measurable). Measurements/ evaluations must be done within 28 days prior to randomization.
- Prior FDG-PET scan, if done at baseline, must be positive (known FDG-avid lymphoma)
- Patients with de novo aggressive B-cell lymphoma must have relapsed or progressed, or have refractory disease, after 1 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 age is ≥16 years. Patients older than 65 years of age are not recommended for this study.
- ECOG performance status of 0, 1 or 2.
- Patient must be considered fit for intensive chemotherapy and ASCT, and an appropriate candidate to receive second-line salvage chemotherapy and ASCT.
- Life expectancy > 90 days.
- Laboratory Requirements: (must be done within 14 days of randomization)
Hematology:
- Granulocytes (AGC) ≥ 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)
Biochemistry:
- AST and ALT ≤ 3x ULN (if both are done, both must be <3x UNL)
- Serum total bilirubin ≤ 1.5x ULN (≤ 5x ULN if Gilberts Disease)
- Serum Creatinine ≤ 1.5x ULN (or estimated GFR of ≥ 40 mL/min/1.73m2 using Cockcroft Gault formula).
Women must be post-menopausal, surgically sterile or use reliable forms of contraception while on study. Women of child bearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. These restrictions apply for 12 months (1 year) after the last dose of study drug.
- Women of childbearing potential must have a pregnancy test taken (either by serum beta-human chorionic gonadotropin [B-hCG]) or urine) and proven negative within 14 days prior to randomization. Women who are pregnant or breastfeeding are ineligible for this study.
Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.
Patients must be accessible for treatment and follow up. Patients randomized on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, response assessment, adverse events, and follow-up.
In accordance with CCTG policy, protocol treatment is to begin within 5 working days of patient randomization.
Exclusion Criteria:
- Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer and superficial bladder cancer, curatively treated in-situ cancer of the cervix or breast, or localized excised prostate cancer, other solid tumours curatively treated with no evidence of disease for ≥ 3 years.
- 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.
- Major surgery performed within 10 days of randomization.
- Known history of human immunodeficiency virus (HIV), active Hepatitis C Virus infection, active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics. 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 past history of hepatitis C who have eradicated the virus are eligible.
- Patients who have been vaccinated with live, attenuated vaccines within 4 weeks of randomization.
- Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
- Any serious active disease or co-morbid medical condition, including psychiatric illness, judged by the local investigator to preclude safe administration of the planned protocol treatment or required follow-up.
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Any other serious intercurrent illness, life threatening condition, organ system dysfunction, or medical condition judged by the local investigator to compromise the subject's safety, interfere with the absorption or metabolism of selinexor tablets, or preclude safe administration of the planned protocol treatment or required follow-up, including (for example):
- active, uncontrolled bacterial, fungal, or viral infection;
- clinically significant cardiac dysfunction or cardiovascular disease.
- 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.
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 ClinicalTrials.gov identifier (NCT number): NCT02436707
| Contact: Annette Hay | 613-533-6430 | ahay@ctg.queensu.ca |
| Canada, Alberta | |
| Tom Baker Cancer Centre | Recruiting |
| Calgary, Alberta, Canada, T2N 4N2 | |
| Contact: Douglas A. Stewart 403 521-3347 | |
| Cross Cancer Institute | Recruiting |
| Edmonton, Alberta, Canada, T6G 1Z2 | |
| Contact: Neil Sun Chua 780 432-8340 | |
| Canada, British Columbia | |
| BCCA - Vancouver Cancer Centre | Recruiting |
| Vancouver, British Columbia, Canada, V5Z 4E6 | |
| Contact: Diego Villa Restrepo 604 877-6000 ext 2740 | |
| Canada, Manitoba | |
| CancerCare Manitoba | Recruiting |
| Winnipeg, Manitoba, Canada, R3E 0V9 | |
| Contact: Pamela Skrabek 204 787-2368 | |
| Canada, New Brunswick | |
| The Moncton Hospital | Suspended |
| Moncton, New Brunswick, Canada, E1C 6Z8 | |
| Canada, Nova Scotia | |
| QEII Health Sciences Centre | Recruiting |
| Halifax, Nova Scotia, Canada, B3H 1V7 | |
| Contact: Mary-Margaret Keating 902 473-7006 | |
| Canada, Ontario | |
| Juravinski Cancer Centre at Hamilton Health Sciences | Recruiting |
| Hamilton, Ontario, Canada, L8V 5C2 | |
| Contact: Graeme Fraser 905 575-7820 | |
| Kingston Health Sciences Centre | Recruiting |
| Kingston, Ontario, Canada, K7L 2V7 | |
| Contact: Jill Dudebout 613 533-2946 | |
| Ottawa Hospital Research Institute | Recruiting |
| Ottawa, Ontario, Canada, K1H 8L6 | |
| Contact: Isabelle Bence-Bruckler 613 737-8152 | |
| Odette Cancer Centre | Recruiting |
| Toronto, Ontario, Canada, M4N 3M5 | |
| Contact: Matthew Cheung 416 480-5000 ext 4757 | |
| University Health Network | Recruiting |
| Toronto, Ontario, Canada, M5G 2M9 | |
| Contact: John Kuruvilla 416 946-2827 | |
| Canada, Quebec | |
| CIUSSS de l'Est-de-I'lle-de-Montreal | Suspended |
| Montreal, Quebec, Canada, H1T 2M4 | |
| CHUM-Centre Hospitalier de l'Universite de Montreal | Recruiting |
| Montreal, Quebec, Canada, H2X 3E4 | |
| Contact: Stephane Doucet 514 890-8444 | |
| CHU de Quebec-Hopital l'Enfant-Jesus (HEJ) | Recruiting |
| Quebec City, Quebec, Canada, G1J 1Z4 | |
| Contact: Jean-Francois Larouche | |
| Canada, Saskatchewan | |
| Allan Blair Cancer Centre | Recruiting |
| Regina, Saskatchewan, Canada, S4T 7T1 | |
| Contact: Muhammad Aslam 306 766-2691 | |
| Study Chair: | Michael Crump | Univ. Health Network-OCI/Princess Margaret Hospital, Toronto ON Canada | |
| Study Chair: | John Kuruvilla | Univ. Health Network-Princess Margaret Hospital, Toronto ON Canada |
| Responsible Party: | Canadian Cancer Trials Group |
| ClinicalTrials.gov Identifier: | NCT02436707 |
| Other Study ID Numbers: |
LY17 |
| First Posted: | May 7, 2015 Key Record Dates |
| Last Update Posted: | May 10, 2022 |
| Last Verified: | July 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Plan Description: | Subject to CCTG Policy |
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Lymphoma Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Dexamethasone Cyclophosphamide Rituximab Gemcitabine Etoposide Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |
Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Antineoplastic Agents, Immunological Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents Gastrointestinal Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists |