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Acalabrutinib-Lenalidomide-Rituximab in Patients With Untreated MCL

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ClinicalTrials.gov Identifier: NCT03863184
Recruitment Status : Not yet recruiting
First Posted : March 5, 2019
Last Update Posted : June 21, 2019
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Brief Summary:

This clinical trial is for men and women age 18 and older with Mantle Cell Lymphoma (MCL) to check efficacy and safety of the combination of Acalabrutinib, Lenalidomide and Rituximab (ALR) in previously untreated Mantle Cell Lymphoma.

Mantle Cell Lymphoma is a type of cancer that the body makes abnormal B-cells (white blood cells) responsible for fighting infections. Mantle Cell Lymphoma is incurable, with a median survival of 5-7 years. Therefore, there is a need to find more effective treatments with fewer side effects.

Both Lenalidomide-based and Acalabrutinib inhibitor-based regimens have demonstrated significant clinical activities in MCL patients. The clinical and non-clinical observations suggest that Acalabrutinib-Lenalidomide-Rituximab combined therapy may produce superior antitumor activity compared to one drug alone.

  • Study Arms: single arm study.
  • Patients will take medication orally and intravenous (IV). Cycles will be 1-12, 1 cycle= 28 days.
  • All patients will be followed for survival until end of study or until sponsor ends the study.
  • Will continue on treatment as long as they are responding to therapy and not experiencing unacceptable side effects.

Key eligibility:

  • Open to men and women 18 years and older
  • Pathologically confirmed Mantle Cell Lymphoma
  • No prior systemic therapy for lymphoma
  • Detailed eligibility reviewed when you contact the study team.

Condition or disease Intervention/treatment Phase
Mantle Cell Lymphoma Drug: Acalabrutinib Drug: Lenalidomide Drug: Rituximab Phase 2

Detailed Description:

This is a single-arm phase 2 study to evaluate the preliminary evidence of efficacy and safety of the combination of acalabrutinib, lenalidomide and rituximab (ALR) in previously untreated mantle cell lymphoma, as well as the feasibility of treatment intensity adapted to MRD status.

Study intervention starts with an induction phase consisting of 12 cycles of ALR. Subjects that do not experience progressive disease will be eligible to enter a maintenance phase involving continued ALR until they achieve an MRD-negative CR, disease progression or unacceptable toxicity occurs.

Subjects will be monitored for MRD status in PB every 16 weeks during maintenance phase. Subjects achieving MRD-negative CR at any time after induction will be eligible to stop acalabrutinib and lenalidomide while continuing rituximab maintenance every 8 weeks. Subjects on rituximab maintenance will be eligible for retreatment with acalabrutinib and lenalidomide at time of either molecular or clinical progression, and continue until MRD-negative CR or disease progression.

Subjects with no detectable MRD at baseline will receive 12 cycles of ALR induction followed by up to 12 cycles of maintenance ALR. They are eligible to stop both acalabrutinib and lenalidomide if in clinical CR, or stop lenalidomide alone if in clinical PR. These subjects will not be eligible for retreatment.

Subjects will be followed after completing study intervention every 6 months for alternate anti-cancer therapy and survival.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Study intervention begins with 12 cycles of acalabrutinib, lenalidomide and rituximab (ALR) in combination (induction phase), which is followed by a maintenance phase of continued ALR until achieving an MRD-negative CR. Subjects achieving MRD-negative CR at any time after induction will be eligible to stop acalabrutinib and lenalidomide while continuing rituximab maintenance every 8 weeks. Subjects on rituximab maintenance will be eligible for retreatment with acalabrutinib and lenalidomide at time of either molecular or clinical progression, and continue until MRD-negative CR or disease progression. Subjects with no detectable MRD at baseline will receive 12 cycles of ALR induction followed by up to 12 cycles of maintenance ALR. They are eligible to stop both acalabrutinib and lenalidomide if in clinical CR, or stop lenalidomide alone if in clinical PR. These subjects will not be eligible for retreatment.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multiple-center Phase 2 Study of Acalabrutinib-Lenalidomide-Rituximab With Real-time MRD Monitoring in Patients With Previous Untreated Mantle Cell Lymphoma
Estimated Study Start Date : September 1, 2019
Estimated Primary Completion Date : September 1, 2022
Estimated Study Completion Date : September 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: ALR in Combination
Acalabrutinib, lenalidomide, and rituximab in combination
Drug: Acalabrutinib
Acalabrutinib, oral, 100 mg BID, continuous, may be discontinued upon MRD-negative CR, and may be re-treated at time of molecular or clinical progression for subjects with prior MRD-negative CR
Other Names:
  • CALQUENCE
  • ACP-196

Drug: Lenalidomide
Lenalidomide, 15 mg for cycle 1, then escalated as tolerated to 20 mg, QD, Days 1-21 out of 28 day cycles, may be discontinued upon MRD-negative CR, and may be re-treated at time of molecular or clinical progression for subjects with prior MRD-negative CR
Other Name: Revlimid

Drug: Rituximab
Rituximab, IV, weekly during Cycle 1, and every other cycle starting with Cycle 4
Other Name: Rituxan




Primary Outcome Measures :
  1. Minimum residual disease (MRD)-negative CR rate of the combination of acalabrutinib + lenalidomide + rituximab at the conclusion of 12 cycles of induction therapy [ Time Frame: 1 year ]
    Percentage of subjects with MRD-negative CR at the conclusion of 12 cycles of induction therapy. Each cycle is 28 days, 12 cycles is approximately 1 year.


Secondary Outcome Measures :
  1. Safety of combination treatment with acalabrutinib, lenalidomide, and rituximab as measured by the percentage of subjects that experience 1 or more adverse event [ Time Frame: 4 years ]
    Rate of subjects that experience 1 or more adverse events

  2. Overall response rate [ Time Frame: 4 years ]
    Rate of subjects who achieve a partial or complete response

  3. Complete response rate [ Time Frame: 4 years ]
    Rate of subjects who achieve a complete response

  4. Progression free survival [ Time Frame: 4 years ]
    Measured from start of treatment to time of progression or death from any cause, measured in months

  5. Overall survival [ Time Frame: 4 years ]
    Measured from start of treatment to death from any cause, measured in months

  6. Rate of subjects who achieve MRD-negative CR after the first re-treatment [ Time Frame: 4 years ]
    Rate of subjects who achieve MRD-negative CR after the first re-treatment



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

Inclusion Criteria:

  • Histologically confirmed diagnosis of mantle cell lymphoma
  • Age ≥ 18 years
  • No prior systemic therapy for lymphoma
  • Patient has measurable disease defined by a tumor mass ≥ 1.5 cm in one dimension and measurable in two dimensions; patient with measurable spleen disease is allowed
  • Treatment should be indicated according to the treating physician
  • ECOG performance status ≤ 2
  • Required initial laboratory parameters:

    • Absolute neutrophil count (ANC) ≥ 1000 cells/mm3
    • Platelet count ≥ 75,000 cells/mm3
    • Calculated creatinine clearance ≥ 30 ml/min by Cockcroft-Gault formula
    • Total bilirubin ≤ 2.0 x ULN
    • AST/SGOT or ALT/SGPT ≤ 3.0 x ULN
  • Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use low molecular weight heparin).
  • All subjects must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of Revlimid REMS®.
  • Patients of reproductive potential agree to use birth control throughout their participation in this study, and for 28 days following study termination.
  • Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days). FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before and continue for at least 28 days after the last dose of lenalidomide (or 2 days after the last dose of acalabrutinib, whichever is longer). FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual activity with a FCBP through one week post last dose even if they have had a successful vasectomy. Men must also agree to refrain from sperm donation during the same timeframe. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.
  • Understand and voluntarily sign an ICF prior to any study related assessments and procedures are conducted.
  • Able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

  • Patients with blastoid histology
  • Patients with known or suspected CNS involvement
  • Active viral infection with HIV or hepatitis type B or C. Seropositive HBV patients are eligible if they are negative for HBV DNA by PCR and receive concomitant antiviral therapy during treatment and for additional six months after coming off study.
  • Prior history of malignancies other than MCL unless the patient has been disease free for ≥ 5 years from the signing of the ICF. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin; carcinoma in situ of cervix; carcinoma in situ of breast, or localized prostate cancer
  • Active uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment)
  • 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 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
  • Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
  • Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand disease).
  • Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura).
  • Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.
  • Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
  • Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) >2x ULN.
  • Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
  • History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug.
  • Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
  • Patients with a history of toxic epidermal necrolysis or Stevens-Johnson syndrome
  • Patients that are pregnant or breast feeding
  • Known hypersensitivity to any study drug or excipients
  • Patient on corticosteroids within two weeks prior to study entry, except for prednisone ≤ 20 mg/day or equivalent for purposes other than treating MCL
  • Use of any other experimental drug or therapy within 28 days of baseline
  • Patient at high risk for deep vein thrombosis not willing to take DVT prophylaxis
  • Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
  • Known prior exposure to BTK inhibitor

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 ClinicalTrials.gov identifier (NCT number): NCT03863184


Contacts
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Contact: Amelyn Rodriguez, R.N. 2127461362 amr2017@med.cornell.edu
Contact: Rita Vaccaro, R.N. 2127460702 rig9021@med.cornell.edu

Locations
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United States, New York
Weill Cornell Medicine
New York, New York, United States, 10065
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
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Principal Investigator: Jia Ruan, M.D., Ph.D. Weill Cornell Medicine

Additional Information:
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Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT03863184     History of Changes
Other Study ID Numbers: 1807019439
First Posted: March 5, 2019    Key Record Dates
Last Update Posted: June 21, 2019
Last Verified: June 2019
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

Keywords provided by Weill Medical College of Cornell University:
MRD
Minimal-residual-disease
Treatment naive
Untreated
Frontline
Acalabrutinib
Lenalidomide
Rituximab

Additional relevant MeSH terms:
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Lenalidomide
Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors