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Obinutuzumab in Combination With Ibrutinib in Treating Patients With Relapsed Mantle Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT02736617
Recruitment Status : Recruiting
First Posted : April 13, 2016
Last Update Posted : September 25, 2017
Sponsor:
Collaborators:
Genentech, Inc.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Stephen Spurgeon, OHSU Knight Cancer Institute

Brief Summary:
This phase II trial studies how well obinutuzumab works in combination with ibrutinib in treating patients with mantle cell lymphoma that has returned (relapsed) or that does not respond to treatment (refractory). Obinutuzumab binds to a protein called cluster of differentiation (CD)20, which is found on B cells and some types of leukemia and lymphoma cells and help the immune system kill cancer cells. Ibrutinib blocks a protein called Bruton's tyrosine kinase (BTK), which may help keep cancer cells from growing. Giving obinutuzumab in combination with ibrutinib may kill more cancer cells.

Condition or disease Intervention/treatment Phase
Recurrent Mantle Cell Lymphoma Refractory Mantle Cell Lymphoma Drug: Ibrutinib Other: Laboratory Biomarker Analysis Biological: Obinutuzumab Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Best overall response of complete response/partial response (CR/PR).

SECONDARY OBJECTIVES:

I. Toxicity defined as any adverse event (AE) grade 3 and higher. II. Progression free survival.

TERTIARY OBJECTIVES:

I. Gene expression profiling using Lymph5Cx test. II. Sequencing using the ion torrent platform (76 gene panel for known mutations in lymphoma).

III. Sequencing of BTK to evaluate for BTK mutations. IV. Minimal residual disease testing (MRD by flow cytometry and targeted sequencing post treatment).

OUTLINE:

Patients receive obinutuzumab intravenously (IV) over 30 minutes on days 1, 8, 15 (course 1) and day 1 (courses 2-6). Patients also receive ibrutinib orally (PO) once daily (QD) beginning on day 1 (course 1). Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving partial response (PR) continue to receive obinutuzumab IV every 2 months and ibrutinib PO QD for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 5 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Obinutuzumab (GA-101) in Combination With Ibrutinib (I) for the Treatment of Relapsed Mantle Cell Lymphoma
Study Start Date : May 2016
Estimated Primary Completion Date : July 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Treatment (obinutuzumab and ibrutinib)
Patients receive obinutuzumab IV on days 1, 8, 15 and ibrutinib PO QD of first treatment course. Patients then receive obinutuzumab IV on day 1 and ibrutinib PO QD from 2-6 treatment courses. Patients who have PR continue to receive obinutuzumab IV every 2 months and ibrutinib PO QD for 2 years 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

Biological: Obinutuzumab
Given IV
Other Names:
  • Anti-CD20 Monoclonal Antibody R7159
  • GA-101
  • GA101
  • Gazyva
  • huMAB(CD20)
  • R7159
  • RO 5072759




Primary Outcome Measures :
  1. Best overall response of CR/PR, measured from the start of treatment until disease progression/recurrence [ Time Frame: Up to 5 years ]
    A point and interval estimate (95% confidence interval) will be provided.


Secondary Outcome Measures :
  1. Incidence of toxicity, defined as any adverse event grade 3 or higher, classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]
  2. Progression free survival (PFS) [ Time Frame: Time from the first day of combined study treatment (obinutuzumab plus ibrutinib -day 16 of course 1) to disease progression or death within 30 days of the last study drug administration, whichever occurs first, assessed up to 5 years ]
    Kaplan-Meier method will be used to estimate PFS.


Other Outcome Measures:
  1. Gene expression profiling using Lymph5Cx test [ Time Frame: At baseline ]
  2. MRD by flow cytometry and next generation sequencing post treatment [ Time Frame: At baseline ]
    A logrank test will be used to compare PFS between patients with and without MRD negativity after induction (obinutuzumab plus ibrutinib) treatment.

  3. Sequencing of BTK to evaluate for BTK mutations [ Time Frame: At baseline ]
    A chi-square test will be used to compare the ORR between patients with and without BTK mutations.

  4. Sequencing using the ion torrent platform (for MRD and known mutations in lymphoma) [ Time Frame: At baseline ]
    A logrank test will be used to compare PFS between patients with and without MRD negativity after induction (obinutuzumab plus ibrutinib) treatment.



Information from the National Library of Medicine

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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:

  • Subjects must have a diagnosis of relapsed or refractory mantle cell lymphoma as follows:

    • Diagnosis of mantle cell lymphoma (MCL) must include morphology and expression of either cyclin D1 in association with other relevant markers (eg, CD19, CD20, CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR)
    • Relapsed or refractory disease is defined as no response or progressive disease to prior treatment if the prior treatment comprised any of the following:

      • 1 regimen containing an anti-CD20 antibody administered for >= 2 doses, and/or
      • >= 1 regimen containing 1 cytotoxic agent (e.g., bendamustine, chlorambucil, cyclophosphamide, cytarabine, doxorubicin) administered for 2 cycles
  • At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma (Cheson Criteria); the site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement or greater than 1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Absolute neutrophil count (ANC) >= 1.0 K/cu mm; for subjects with ANC < 1.0 K/cu mm due to significant marrow involvement by MCL, ANC must be > .5 K/cu mm
  • Platelets (plt) >= 50 K/cu mm; for subjects with plt < 50 K/cu mm due to significant marrow involvement by MCL, plt must be > 25 K/cu mm
  • Total bilirubin =< 2.5 X institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Creatinine < or = 2
  • Women of childbearing 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; for females, these restrictions apply for 12 months after last dose of obinutuzumab, or 1 month after the last dose of ibrutinib, whichever is later; for males, these restrictions apply for 12 months after the last dose of obinutuzumab or 3 months after the last dose of ibrutinib, whichever is later
  • Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening; women who are pregnant or breastfeeding are ineligible for this study
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Major surgery within 4 weeks of drug administration
  • Known central nervous system lymphoma
  • Diagnosed or treated for malignancy other than MCL, except:

    • Malignancy treated with curative intent and with no known active disease present for >= 2 years before randomization
    • Adequately treated non-melanoma skin cancer or melanoma in situ without evidence of disease
    • Adequately treated cervical carcinoma in situ without evidence of disease
    • Asymptomatic prostate cancer managed with "active surveillance"
  • History of stroke or intracranial hemorrhage within 6 months prior to randomization
  • Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon)
  • Vaccinated with live, attenuated vaccines within 4 weeks of randomization
  • Requires treatment with strong cytochrome P450 3A (CYP3A) inhibitors
  • Subjects who have had standard cytotoxic chemotherapy or radiotherapy within 4 weeks prior to entering the study or those whose adverse events due to agents administered more than 4 weeks earlier have not recovered to =< grade 1; this excludes alopecia and hematologic adverse events
  • Subjects who have received investigational or approved oral or "targeted" agents (such as spleen tyrosine kinase [SYK], phosphatidylinositol 3 kinase [PI3K], B-cell chronic lymphocytic leukemia [CLL]/lymphoma 2 [bcl-2], BTK inhibitors) or lenalidomide within 1 week prior to entering the study or those whose adverse events due to agents administered more than 1 week earlier have not recovered to =< grade 1; this excludes hematologic adverse events
  • Subjects who have received monoclonal antibodies (such as Rituxan) within 1 week prior to entering the study or those whose adverse events due to agents administered more than 1 week earlier have not recovered to =< grade 1; this excludes hematologic adverse events
  • Subjects who are actively receiving any other investigational agents
  • History of severe allergic reactions attributed to compounds of similar chemical or biologic composition as obinutuzumab or ibrutinib or other agents used in the study
  • Uncontrolled intercurrent 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
  • Pregnant or lactating women are excluded from this study
  • Known history of human immunodeficiency virus (HIV) or active hepatitis C
  • Virus or active hepatitis B virus infection; patients who are hepatitis B core antibody (Hep B cAb) positive may be eligible as long as there is no evidence of active infection with negative hepatitis B (Hep B) by polymerase chain reaction (PCR); in this case, Hep B PCR must be monitored monthly
  • Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics
  • Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
  • Patients previously treated with ibrutinib > 14 days are ineligible; if patient has been treated with ibrutinib for < 14 days, it must be discontinued 1 week (7 days) weeks prior to study initiation
  • Active graft versus (vs.) host disease (gvhd)
  • Ongoing glucocorticoids (prednisone > 10 mg daily, or equivalent); higher doses (> 10 mg daily) are permitted for up to 5 days to help control disease related symptoms

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): NCT02736617


Locations
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United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: Stephen E. Spurgeon    503-494-8950    spurgeos@ohsu.edu   
Principal Investigator: Stephen E. Spurgeon         
Sponsors and Collaborators
OHSU Knight Cancer Institute
Genentech, Inc.
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Stephen Spurgeon OHSU Knight Cancer Institute

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Responsible Party: Stephen Spurgeon, Associate Professor, OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT02736617     History of Changes
Other Study ID Numbers: STUDY00015255
NCI-2016-00398 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STUDY00015255 ( Other Identifier: OHSU Knight Cancer Institute )
P30CA069533 ( U.S. NIH Grant/Contract )
First Posted: April 13, 2016    Key Record Dates
Last Update Posted: September 25, 2017
Last Verified: September 2017
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Obinutuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents