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

• ClinicalTrials.gov Identifier: NCT03323151
• Recruitment Status: Active, not recruiting
• First Posted: October 26, 2017
• Last Update Posted: November 21, 2022
• Sponsor: PrECOG, LLC.
• Collaborator: Takeda
• Information provided by (Responsible Party): PrECOG, LLC.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Mantle-Cell Lymphoma	Drug: Ixazomib; Drug: Ibrutinib	Phase 1; Phase 2

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.

8/7/2020: Enrollment stopped to patients who have already received a BTK inhibitor. Total of two patients enrolled (1 in Phase I and 1 in Phase II).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 43 participants
• 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-naïve and BTK-pretreated (BTK pretreated closed 8/7/2020) .

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma
• Actual Study Start Date: August 13, 2018
• Actual Primary Completion Date: September 22, 2022
• Estimated Study Completion Date: July 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase I: Ixazomib & Ibrutinib; Ixazomib and Ibrutinib will be given by mouth until progression or unacceptable toxicity.	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: 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
Experimental: Phase II: Ixazomib & BTK-Naive; Patients who are BTK-Naive will receive Ixazomib and Ibrutinib by mouth until progression or unacceptable toxicity.	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 until progression or unacceptable toxicity.; Other Name: Imbruvica
Experimental: Phase II: Ixazomib & BTK Pre-Treated (Closed 8/7/2020); Patients previously treated with a BTK will receive Ixazomib and Ibrutinib by mouth until progression or unacceptable toxicity.	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 until progression or unacceptable toxicity.; Other Name: Imbruvica

Outcome Measures

Primary Outcome Measures :

1. Phase I: Maximum Tolerated Dose (MTD) [ Time Frame: 1 month ]
   MTD of ixazomib in mg in combination with ibrutinib in mg
2. Phase II: Complete Response Rate [ Time Frame: 12 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.

Secondary Outcome Measures :

1. 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
2. Overall Response Rate (ORR) [ Time Frame: Phase I: 12 months; Phase II: 12 months ]
   ORR assessed in accordance with Lugano classification
3. Progression-Free Survival (PFS) [ Time Frame: Phase I: 15 months; Phase II: 60 months ]
   PFS assessed in accordance with Lugano classification
4. Overall Survival (OS) [ Time Frame: Phase I: 15 months; Phase II: 60 months ]
   OS assessed in accordance with Lugano classification

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• 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 inhibitors allowed. (Please note prior to Version 3.0 of the protocol prior proteasome inhibitor and/or Bruton's tyrosine kinase inhibitors were allowed but patients could not have been exposed to the combination of proteasome inhibitor and BTK inhibitor).
• 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.

Contacts and Locations

Locations

United States, Georgia

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States, 30322

Georgia Cancer Center at Augusta University

Augusta, Georgia, United States, 30912

United States, Illinois

Carle Cancer Center

Urbana, Illinois, United States, 61801

United States, Kansas

University of Kansas

Overland Park, Kansas, United States, 66210

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New Jersey

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08903

United States, New York

Laura and Isaac Perlmutter Cancer Center at NYU

New York, New York, United States, 10016

United States, Pennsylvania

University of Pennsylvania Abramson Cancer Center

Philadelphia, Pennsylvania, United States, 19104

United States, Virginia

University of Virginia

Charlottesville, Virginia, United States, 22908

United States, West Virginia

West Virginia University

Morgantown, West Virginia, United States, 26506

United States, Wisconsin

Gundersen Health System

La Crosse, Wisconsin, United States, 54601

University of Wisconsin

Madison, Wisconsin, United States, 53792

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

ProHealth Care

Waukesha, Wisconsin, United States, 53188

Sponsors and Collaborators

PrECOG, LLC.

Takeda

Investigators

• Study Chair: Jonathon B Cohen, MD; Emory University - Winship Cancer Institute

More Information

• Responsible Party: PrECOG, LLC.
• ClinicalTrials.gov Identifier: NCT03323151
• Other Study ID Numbers: PrE0404; X16077 ( Other Identifier: Takeda )
• First Posted: October 26, 2017
• Last Update Posted: November 21, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Data is proprietary.

• 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

Keywords provided by PrECOG, LLC.:

Relapsed Mantle-Cell Lymphoma; Refractory Mantle-Cell Lymphoma; Ixazomib; Ibrutinib; Proteasome Inhibitor; Bruton's Tyrosine Kinase Inhibitor

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Mantle-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Ixazomib; Glycine; Antineoplastic Agents; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Glycine Agents; Neurotransmitter Agents; Physiological Effects of Drugs