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A Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma (PrE0404)

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: NCT03323151
Recruitment Status : Recruiting
First Posted : October 26, 2017
Last Update Posted : March 27, 2020
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
PrECOG, LLC.

Tracking Information
First Submitted Date  ICMJE October 16, 2017
First Posted Date  ICMJE October 26, 2017
Last Update Posted Date March 27, 2020
Actual Study Start Date  ICMJE August 13, 2018
Estimated Primary Completion Date January 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2017)
  • Phase I: Maximum Tolerated Dose (MTD) [ Time Frame: 15 months ]
    MTD of ixazomib in mg in combination with ibrutinib in mg
  • Phase II: Complete Response Rate [ Time Frame: 60 months ]
    CR rate will be the defined as the percentage of patients achieving CR as confirmed by bone marrow biopsy within the first 12 months of initiating treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2020)
  • Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: Phase I: 15 months; Phase II: 60 months ]
    Number of patients with abnormal laboratory values and/or adverse events related to treatment
  • Overall Response Rate (ORR) [ Time Frame: Phase I: 15 months; Phase II: 60 months ]
    ORR assessed in accordance with Lugano classification
  • Progression-Free Survival (PFS) [ Time Frame: Phase I: 15 months; Phase II: 60 months ]
    PFS assessed in accordance with Lugano classification
  • Overall Survival (OS) [ Time Frame: Phase I: 15 months; Phase II: 60 months ]
    OS assessed in accordance with Lugano classification
Original Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2017)
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Phase I: 15 months; Phase II: 60 months ]
    Number of patients with abnormal laboratory values and/or adverse events related to treatment
  • Overall Response Rate (ORR) [ Time Frame: Phase I: 15 months; Phase II: 60 months ]
    ORR assessed in accordance with Lugano classification
  • Progression-Free Survival (PFS) [ Time Frame: Phase I: 15 months; Phase II: 60 months ]
    PFS assessed in accordance with Lugano classification
  • Overall Survival (OS) [ Time Frame: Phase I: 15 months; Phase II: 60 months ]
    OS assessed in accordance with Lugano classification
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma
Official Title  ICMJE A Phase I/II Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma
Brief Summary

Patients with mantle cell lymphoma (MCL) that has relapsed (come back) or refractory (progressed on treatment) will receive ixazomib and ibrutinib.

Ibrutinib has been approved by the Food and Drug Administration (FDA) as treatment for patients with mantle cell lymphoma who have received at least one prior therapy.

Ixazomib is in a class of medications called proteasome inhibitors. Cancer cells depend on proteasome to provide this protein metabolism (turnover) function to regulate their growth and survival. Ixazomib disrupts a cancer cells' ability to survive by blocking the proteasome and disrupting protein metabolism. This may help to slow down the growth of cancer or may cause cancer cells to die.

The purpose of this study is to see whether the addition of ixazomib to ibrutinib chemotherapy is effective in treating people who have relapsed or refractory MCL and to examine the side effects associated with ixazomib in combination with ibrutinib.

Detailed Description

MCL is a rare subtype of non-Hodgkin lymphoma that is considered incurable with conventional therapy. For relapsed patients, Ibrutinib, lenalidomide, and bortezomib are all approved by the FDA but are not curative. Novel approaches are required to improve outcomes for patients with relapsed/refractory MCL.

This is an open-label study that will be done in 2 phases. Phase I will test different doses of ixazomib and ibrutinib to determine the maximum safe and tolerated dose. In Phase I, patients who have already received ibrutinib, may participate if they meet certain criteria (i.e., have not received ibrutinib for at least 3 months).

Phase I was completed November 25, 2019. Dose Level 2 (Ixazomib 4 mg and Ibrutinib 560 mg) is the recommended Phase II dose.

Phase II will find out the effects, good and/or bad, of ixazomib in combination with ibrutinib. In Phase II, patients will be separated into 2 groups, patients who have never received a Bruton's Tyrosine Kinase (BTK) inhibitor and patients who have received a BTK inhibitor. This study is designed to examine the effectiveness of this drug in treating patients with MCL.

Patients will be treated until progression or unacceptable toxicity.

Tumor assessments will be performed approximately every 3 months for the first year of treatment, then every 6 months until progression.

Mandatory bone marrow and tumor tissue samples (i.e., obtained during a previous procedure or biopsy) are required at baseline. Mandatory research blood samples will also be collected.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Phase I: Standard 3+3 design with the primary objective of determining the maximum tolerate dose (MTD)/recommended phase 2 dose (RP2D) of this combination in MCL. Both ibrutinib-pretreated and ibrutinib-naïve patients will be enrolled.

Phase II: Dose Level 2 is the RP2D. Patients will be enrolled to two cohorts, based on prior ibrutinib treatment: BTK-pretreated and BTK-naïve.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Mantle-Cell Lymphoma
Intervention  ICMJE
  • Drug: Ixazomib
    Ixazomib 3 mg by mouth on days 1, 8 and 15 by mouth days 1-28 of a 28 day cycle. Dose may be de-escalated (Ixazomib 3 mg) or escalated (Ixazomib 4 mg) dependent on dose-limiting toxicities.
    Other Name: Ninlaro
  • Drug: Ixazomib
    Ixazomib 4 mg by mouth on days 1, 8 and 15 of a 28 day cycle until progression or unacceptable toxicity.
    Other Name: Ninlaro
  • Drug: Ibrutinib
    Ibrutinib 560 mg by mouth days 1-28 of a 28 day cycle. Dose may be de-escalated (Ibrutinib 420 mg) or escalated (Ibrutinib 560 mg) dependent on dose-limiting toxicities.
    Other Name: Imbruvica
  • Drug: Ibrutinib
    Ibrutinib 560 mg by mouth days 1-28 of a 28 day cycle until progression or unacceptable toxicity.
    Other Name: Imbruvica
Study Arms  ICMJE
  • Experimental: Phase I: Ixazomib & Ibrutinib
    Ixazomib and Ibrutinib will be given by mouth until progression or unacceptable toxicity.
    Interventions:
    • Drug: Ixazomib
    • Drug: Ibrutinib
  • Experimental: Phase II: Ixazomib & BTK-Naive
    Patients who are BTK-Naive will receive Ixazomib and Ibrutinib by mouth until progression or unacceptable toxicity.
    Interventions:
    • Drug: Ixazomib
    • Drug: Ibrutinib
  • Experimental: Phase II: Ixazomib & BTK Pre-Treated
    Patients previously treated with a BTK will receive Ixazomib and Ibrutinib by mouth until progression or unacceptable toxicity.
    Interventions:
    • Drug: Ixazomib
    • Drug: Ibrutinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 23, 2017)
84
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2024
Estimated Primary Completion Date January 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • Relapsed or refractory, pathologically proven mantle cell lymphoma. Must have a current or prior tissue sample that is IHC positive for cyclin D 1 or that is positive by FISH or cytogenetics for t(11;14).
  • Must have been refractory to and/or relapsed/progressed after at least 1 prior therapy.
  • Prior autologous or allogeneic transplant are allowed. Patients may not have active grade II-IV acute graft-versus-host disease (GVHD) or moderate/severe chronic GVHD by NIH criteria and may not require immunosuppressive medications and/or corticosteroids for the management of acute or chronic GVHD.
  • Phase I: Prior proteasome inhibitor and/or Bruton's tyrosine kinase (BTK) inhibitors are allowed but patients may not have been exposed to the combination of proteasome inhibitor and BTK inhibitor. Patients who have progressed on ibrutinib that are felt to be at high risk for rapid progression on this study shall not be eligible for the phase I portion of the study. NOTE: Ibrutinib pre-treated patients must meet all eligibility criteria AND must have discontinued prior ibrutinib at least 3 months prior to starting study therapy. PHASE I COMPLETED NOVEMBER 25, 2019.
  • Phase II: Prior proteasome inhibitor and/or Bruton's tyrosine kinase inhibitors are allowed but patients may not have been exposed to the combination of proteasome inhibitor and BTK inhibitor. NOTE: Patients in the BTK-pretreated cohort must have tolerated prior ibrutinib or other BTK inhibitor (i.e., not discontinued therapy due to a toxicity that is still ongoing). Patients who discontinued a BTK inhibitor due to toxicity that has been treated and resolved and for which it is considered appropriate to re-challenge the patient with ibrutinib may be enrolled if the investigator provides documentation explaining why they feel re-challenging with ibrutinib is clinically appropriate. Such patients would only be enrolled after approval of the PrECOG Medical Monitor & Study Chair.
  • Age ≥ 18 years.
  • Eastern Oncology Oncology Group (ECOG) performance status of 0-2.
  • Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent.
  • Willing to provide archived tumor tissue, bone marrow (if sufficient bone marrow and tumor tissue are available) and blood samples for research.
  • Adequate organ function as measured by the following criteria

    • Absolute Neutrophil Count (ANC) ≥ 750/mm³
    • Platelets ˃50,000/mm³
    • Serum Creatinine ≤ 2x Upper Limit Normal (ULN)
    • ALT and AST ≤ 3x ULN
    • Total Bilirubin ≤ 1.5x ULN
  • Patients must not have received systemic treatment for MCL for at least 14 days prior to enrollment, except for steroids which may be used to manage acute symptoms related to disease up to 48 hours prior to starting study therapy. Radiation therapy must be concluded at least 14 days prior to enrollment.
  • Women must not be pregnant or breastfeeding since we do not know the effects of ixazomib and ibrutinib on the fetus or breastfeeding child. All sexually active females of childbearing potential must have a blood test to rule out pregnancy within 2 weeks prior to registration.
  • Sexually active women of child-bearing potential with a non-sterilized male partner and sexually active men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 3 months following last dose of study drugs.
  • Patients must have resolved all prior non-hematologic toxicities assessed as related to prior therapy to ≤ grade 1.
  • Patients must have measurable disease (i.e., ≥ 1.5 cm in largest diameter) by conventional imaging modalities. Patients with extranodal involvement as the only measurable site of disease must have a largest diameter ≥ 1.0 cm and must be attributable to active lymphoma in the opinion of the investigator.
  • Patients may not have current/active Central Nervous System (CNS) involvement with mantle cell lymphoma (patients with prior CNS involvement are eligible as long as they have had no evidence of active CNS disease for at least 6 months).
  • Patients may not have another malignancy that could interfere with the evaluation of safety or efficacy of this combination. Patients with a prior malignancy will be allowed without study chair approval in the following circumstances:

    • Not currently active and diagnosed at least 3 years prior to the date of enrollment.
    • Non-invasive diseases such as low risk cervical cancer or any cancer in situ
    • Localized disease in which chemotherapy would not be indicated (such as Stage I colon, lung, prostate or breast cancer). Patients with other malignancies not meeting these criteria must be discussed with PrECOG prior to enrollment.
  • Patients requiring long-term anticoagulation must be managed on an anticoagulant besides warfarin. Patients who require warfarin are not eligible.
  • Patients with a clinically significant bleeding episode as judged by the investigator within 3 months of registration are not eligible, except patients who suffer bleeding due to trauma.
  • Patients may not have had major surgery within 14 days, or minor surgery within 3 days, before registration.
  • Patients may not have any active infection requiring oral or intravenous antimicrobial therapy at the time of therapy initiation. Patients with a recent self-limited infection that has clinically resolved may complete a prescribed course of antimicrobial therapy after study initiation as long as they are asymptomatic with no clinical evidence of infection for at least 7 days prior to treatment. Patients with a recent serious (grade ≥ 3) infection requiring hospitalization must have completed all antimicrobial therapy within 14 days of therapy initiation.
  • Patients may not have evidence of uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure (New York Heart Association (NYHA) class III or higher, unstable angina, or myocardial infarction within the past 6 months. Patients with a history of any significant cardiovascular disease that has been controlled for at least 14 days before registration are allowed (except for patients who have had a myocardial infarction within 6 months).
  • No systemic treatment, within 14 days before the first dose of ibrutinib with moderate or strong inhibitors of CYP3A (Strong Inhibitors: ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, and telithromycin; Moderate Inhibitors: fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprenavir, crizotinib, imatinib, verapamil, ciprofloxacin, grapefruit juice products, and Seville oranges) or strong CYP3A inducers for ibrutinib and ixazomib (carbamazepine, rifampin, phenytoin, St. John's wort).
  • Patients with ongoing or active systemic infection, active hepatitis B or C virus infection, or known Human Immunodeficiency Virus (HIV) positive are not eligible. Testing is not required in absence of clinical suspicion.
  • Patients with a history of hepatitis B or C must have a negative peripheral blood Polymerase Chain Reaction (PCR) and may not be positive for Hepatitis B surface antigen. Patients with cirrhosis or other evidence of liver damage due to Hepatitis B or C are not eligible.
  • Patients with any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of the treatment according to the protocol are not eligible.
  • Patients with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent are not eligible.
  • Patients with known gastrointestinal (GI) disease or prior GI procedure that could interfere with the oral absorption or tolerance of ixazomib or ibrutinib including difficulty swallowing are not eligible.
  • Patients with ≥ Grade 2 peripheral neuropathy, or Grade 1 peripheral neuropathy with pain on clinical examination during the screening period are not eligible.
  • Patients may not participate in any other therapeutic clinical trials, including those with other investigational agents not included in this trial throughout the duration of this study.
  • As ibrutinib will not be provided by the study, the patient must be able to obtain ibrutinib through other means (i.e., commercially or through patient assistance programs). This must be confirmed prior to registration.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Carolyn Andrews, RN 267-207-4070 candrews@precogllc.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03323151
Other Study ID Numbers  ICMJE PrE0404
X16077 ( Other Identifier: Takeda )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Data is proprietary.
Responsible Party PrECOG, LLC.
Study Sponsor  ICMJE PrECOG, LLC.
Collaborators  ICMJE Takeda
Investigators  ICMJE
Study Chair: Jonathon B Cohen, MD Emory University - Winship Cancer Institute
PRS Account PrECOG, LLC.
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP