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Ibrutinib and Palbociclib in Treating Patients With Previously Treated Mantle Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT02159755
Recruitment Status : Active, not recruiting
First Posted : June 10, 2014
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies the side effects and best dose of ibrutinib and palbociclib in treating patients with previously treated mantle cell lymphoma. Ibrutinib and palbociclib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Palbociclib may also help ibrutinib work better by making cancer cells more sensitive to the drug.

Condition or disease Intervention/treatment Phase
CCND1 Positive Recurrent Mantle Cell Lymphoma t(11;14) Drug: Ibrutinib Other: Laboratory Biomarker Analysis Drug: Palbociclib Other: Pharmacological Study Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety of ibrutinib plus PD 0332991 (palbociclib) in patients with previously treated mantle cell lymphoma (MCL) and select the recommended phase 2 dose schedule.

SECONDARY OBJECTIVES:

I. To estimate the toxicity profile of ibrutinib plus PD 0332991 (palbociclib). II. To estimate the overall response rate (ORR) and complete response (CR) rates.

III. To estimate the progression-free survival (PFS). IV. To estimate the response duration (RD).

TERTIARY OBJECTIVES:

I. To evaluate the genomic profile of MCL cells pre-treatment and at relapse. II. To estimate the pharmacokinetic profile of ibrutinib when given concurrently with PD 0332991 (palbociclib).

III. To evaluate the level of cell-free tumor deoxyribonucleic acid (DNA) over time in conjunction with response to therapy.

IV. To evaluate the presence of circulating MCL cells over time.

OUTLINE: This is a dose-escalation study.

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 and palbociclib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2 years.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of Ibrutinib Plus PD 0332991 (Palbociclib) in Patients With Previously Treated Mantle Cell Lymphoma
Actual Study Start Date : May 20, 2014
Actual Primary Completion Date : May 11, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Treatment (ibrutinib, palbociclib)
Patients receive ibrutinib PO QD on days 1-28 and palbociclib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Palbociclib
Given PO
Other Names:
  • Ibrance
  • PD-0332991
  • PD-332991

Other: Pharmacological Study
Correlative studies




Primary Outcome Measures :
  1. Recommended phase II dose of the combination of ibrutinib and palbociclib defined as the highest dose level at which no more than 1/6 patients present with a dose limiting toxicity (DLT) [ Time Frame: Up to 28 days ]
    DLT will be assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.


Secondary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 2 years ]
    Will be evaluated according to the revised response criteria of the International Working Group.

  2. Complete response (CR) rate [ Time Frame: Up to 2 years ]
    Will be evaluated according to the revised response criteria of the International Working Group.

  3. Partial response rate [ Time Frame: Up to 2 years ]
    Will be evaluated according to the revised response criteria of the International Working Group.

  4. Progression-free survival (PFS) [ Time Frame: Time from entry onto study until first documentation of objective tumor progression or death due to any cause, whichever occurs first, assessed up to 2 years ]
    Estimated and plotted by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formula. Log-rank test will be applied to compare the difference between survival curves with two-sided significance level of 0.05.

  5. Response duration (RD) [ Time Frame: Time from when criteria for response (CR or partial response [PR]) are met, until first documentation of relapse or progression, assessed up to 2 years ]
    Estimated and plotted by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formula. Log-rank test will be applied to compare the difference between survival curves with two-sided significance level of 0.05.

  6. Incidence of toxicities, assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [ Time Frame: Up to 2 years ]
    A listing of all adverse events (AEs) including detailed information for each AE will be presented. The number and percentage of patients who experienced any: AE, serious adverse events (SAE), treatment-related AE, and treatment-related SAE will be summarized. AE data will be presented by dose for all cycles, cycle 1 only and cycles > 1, as appropriate. Additional summaries of AE data and of other safety data will be presented in tabular and/or graphical format and summarized descriptively, as appropriate.


Other Outcome Measures:
  1. Genetic alterations [ Time Frame: Up to 2 years ]
    Sequencing data will be evaluated for mutations and copy number variations (CNV) and the status of wild type and alterations will be assigned. Fisher's exact test will be used to assess the association between genetic alterations and response to study drugs. A moderated t-test will be applied to the transformed ribonucleic acid sequencing data to assess the expression difference between wild-type and altered genes. The Benjamini-Hochberg procedure will be used to adjust the p value and use the false discovery rate 10% as the cutoff to declare significance.



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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:

  • Patients must have histologically or cytologically confirmed mantle cell lymphoma as defined by the World Health Organization; all patients must have either t(11;14) by karyotype or fluorescent in-situ hybridization (FISH) or positive immunohistochemistry for cyclin D1
  • Subjects must have measurable disease defined as at least one tumor lesion of at least 1.5 cm or a peripheral blood cluster of differentiation (CD)5+, CD19+ lymphocyte count of at least 5,000 cells/uL
  • Subjects must have received at least one prior treatment regimen

    • Subjects that have received a prior Bruton's agammaglobulinemia tyrosine kinase (BTK) inhibitor or cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition are ineligible
    • Subjects that have undergone prior allogeneic stem cell transplantation will only be eligible if the transplant occurred at least 1 year prior to study entry, the patient is no longer taking any immunosuppressive therapy, and there are no significant ongoing transplant-related adverse effects
    • Subjects must not have received chemotherapy =< 21 days prior to first administration of study treatment, monoclonal antibody =< 6 weeks prior to first administration of study treatment, and/or radiotherapy or other investigational agents =< 4 weeks prior to first administration study treatment unless the subjects' tumor has progressed on the previous therapy and the investigator believes that the patient should not postpone further therapy and, all treatment-related toxicities have resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 =< grade 1; subjects may be receiving equivalent to prednisone at a maximum dose of 20 mg/day orally
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Patients must have normal organ and marrow function, independent of transfusion or growth factor support within 14 days before enrollment; patients should not receive growth factors or transfusions for at least 7 days prior to the first dose of study drug, with the exception of pegylated GCSF (pegfilgrastim) and darbepoetin, which require at least 14 days prior to screening and enrollment
  • Absolute neutrophil count (ANC) >= 750 cells/uL within 14 days before enrollment
  • Platelets >= 50,000 cells/uL within 14 days before enrollment
  • Total bilirubin =< 1.5 times upper limit of normal unless due to Gilbert's disease within 14 days before enrollment
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times upper limit of normal within 14 days before enrollment
  • Calculated creatinine clearance >= 30 mL/min by Cockcroft-Gault within 14 days before enrollment
  • Corrected QT interval (QTc) =< 480 ms within 14 days before enrollment
  • Prothrombin time (PT)/international normalized ratio (INR) < 1.5 times upper limit of normal within 14 days before enrollment
  • Partial thromboplastin time (PTT) < 1.5 times upper limit of normal within 14 days before enrollment
  • Subjects with known or suspected central nervous system (CNS) involvement are not eligible
  • Subjects with serologic status reflecting active viral hepatitis B or C infection are not eligible; subjects that are hepatitis B core antibody positive but antigen negative will need negative polymerase chain reaction (PCR) prior to enrollment; PCR-positive patients will be excluded
  • Subjects with uncontrolled human immunodeficiency virus (HIV) are not eligible; controlled HIV is defined as a CD4 count > institutional lower limit of normal and no current co-infection; uncontrolled HIV is all other HIV infection; note that patients with controlled infection should be allowed to participate only if they are not receiving prohibited cytochrome P450 (CYP) interactive medications
  • Subjects unable to swallow capsules or with disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption, such as malabsorption syndrome, resection of the stomach or small bowel, partial or complete bowel obstruction, or symptomatic inflammatory bowel disease are not eligible
  • Subjects with uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements are not eligible; recent infections requiring systemic treatment need to have completed therapy > 14 days before the first dose of the study drugs
  • Subjects with uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP) resulting in declining platelet or hemoglobin levels within the 4 weeks prior to first dose of study drug are not eligible
  • Patients with transfusion-dependent thrombocytopenia are not eligible
  • Subjects with acute coronary syndrome within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities are not eligible; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
  • Subjects with a history of stroke or intracranial hemorrhage within 6 months prior to enrollment are not eligible
  • Subjects with a history of malignancy are not eligible with the exception of the following:

    • Malignancy treated within curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician
    • Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
    • Adequately treated cervical carcinoma in situ without current evidence of disease
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; female patients who are of non-reproductive potential include the following: post-menopausal by history - no menses for >= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); female patients of childbearing potential must have a negative serum pregnancy test upon study entry; male and female patients who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete sexual abstinence, or sterilized partner) during the period of therapy and for 90 days after the last dose of study drug
  • Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ibrutinib administration; subjects should be offered the opportunity to bank sperm or eggs prior to initiation of study drug
  • Female subjects that are pregnant or breastfeeding are not eligible
  • Subjects that have received anticoagulation therapy with warfarin or equivalent vitamin K antagonists within the last 28 days are not eligible
  • Subjects with a bleeding diathesis (e.g., von Willebrand's disease or hemophilia) are not eligible
  • Subjects that have undergone major surgery within 4 weeks prior to the first dose of study drug are not eligible
  • Subjects with currently active, clinically significant hepatic impairment (> moderate hepatic impairment according to the National Cancer Institute (NCI)/Child Pugh classification)
  • Subjects receiving other investigational agents are not eligible
  • Subjects who received a strong cytochrome P450 family 3 subfamily A (CYP3A) inhibitor within 7 days prior to the first dose of study drug, or patients who require continuous treatment with a strong CYP3A inhibitor are not eligible
  • Subjects requiring daily corticosteroids at a prednisone equivalent of > 20 mg daily should not be enrolled; if corticosteroids can be discontinued (or reduced to < 20 mg per day or prednisone equivalent), the discontinuation or dose reduction should be done at least 7 days prior to the first dose
  • Subjects receiving systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc.) within 28 days of the first dose of study drug are not eligible
  • Subjects that have been vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug are not eligible
  • Subjects should be willing to undergo a research related biopsy prior to treatment and at the time of progression
  • Subjects must give informed consent and must be willing and able to comply with the scheduled visits, treatment plans, laboratory tests, and other procedures

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): NCT02159755


Locations
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Weill Medical College of Cornell University
New York, New York, United States, 10065
United States, North Carolina
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Peter Martin Weill Medical College of Cornell University

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02159755     History of Changes
Other Study ID Numbers: NCI-2014-01202
NCI-2014-01202 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
1403014853
9534 ( Other Identifier: Weill Medical College of Cornell University )
9534 ( Other Identifier: CTEP )
K24CA201524 ( U.S. NIH Grant/Contract )
P30CA013696 ( U.S. NIH Grant/Contract )
UM1CA186704 ( U.S. NIH Grant/Contract )
UM1CA186712 ( U.S. NIH Grant/Contract )
First Posted: June 10, 2014    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: July 2018

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
Palbociclib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action