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Study of IPI-145 in Combination With Rituximab or Bendamustine/Rituximab in Hematologic Malignancies

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ClinicalTrials.gov Identifier: NCT01871675
Recruitment Status : Completed
First Posted : June 7, 2013
Last Update Posted : July 11, 2016
Sponsor:
Collaborator:
Infinity Pharmaceuticals, Inc.
Information provided by (Responsible Party):
SCRI Development Innovations, LLC

Brief Summary:
The goal of this study is to characterize the safety, maximum tolerated dose (MTD) and preliminary efficacy profile of IPI-145 given in combination with rituximab, or bendamustine plus rituximab, to subjects with select relapsed/refractory hematologic malignancies.

Condition or disease Intervention/treatment Phase
Lymphoma Chronic Lymphocytic Leukemia Non-Hodgkin Lymphoma T-cell Lymphoma Drug: IPI-145 Drug: Rituximab Drug: Bendamustine Phase 1

Detailed Description:

This trial consists of two parallel arms. For each treatment arm, a 3+3 dose escalation design will be applied in 3-6 subject cohorts until the maximum tolerated dose of IPI-145 when given with rituximab (Arm 1) or in combination with rituximab and bendamustine (Arm 2) is determined. Treatment arm selection will be chosen by the investigator and will depend on the agents previously administered to the subject. Once the MTD has been determined, the arms will move on to a dose expansion phase. During the dose expansion phase, each treatment arm will enroll to population specific cohorts to assess efficacy. All subjects must have had at least one prior anticancer treatment. The dose expansion cohorts are:

Arm 1: Cohort A - CLL: Cohort B - CD20+ NHL

Arm 2: Cohort A - CLL: Cohort B - CD20+ NHL


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Phase Ib Study of IPI-145 in Combination With Rituximab or Bendamustine/Rituximab in Select Subjects With Lymphoma or Chronic Lymphocytic Leukemia
Study Start Date : May 2013
Actual Primary Completion Date : June 2016
Actual Study Completion Date : June 2016


Arm Intervention/treatment
Experimental: Arm 1: IPI-145 plus Rituximab

IPI-145 will be administered orally, twice daily, in 28-day (4-week) cycles, on a continuous basis at the maximum tolerated dose of 25 mg twice-daily (BID), as determined in the dose escalation phase. Twelve (12) cycles of IPI-145 will be administered. Patients who benefit from treatment may continue on study for additional cycles until toxicity or progressive disease.

Rituximab 375 mg/m2 will be administered intravenously (IV) beginning on Day 1 once weekly during a 28 day cycle; 2 cycles of rituximab will be administered.

Drug: IPI-145
Other Name: Duvelisib

Drug: Rituximab
Other Name: Rituxan

Experimental: Arm 2: IPI-145 plus Rituximab/Bendamustine

IPI-145 will be administered orally, twice daily, in 28 day cycles, on a continuous basis, until disease progression, unacceptable toxicity or patient refusal. The maximum tolerated dose of IPI-145 will be 25 mg twice-daily (BID) as determined in the dose escalation phase. Twelve (12) cycles of IPI-145 will be administered. Patients who benefit from treatment may continue on study for additional cycles until toxicity or progressive disease.

Rituximab 375 mg/m2 will be administered intravenously (IV) beginning on Day 1 once weekly of each 28 day cycle. A maximum of 6 cycles of rituximab will be given. Bendamustine 90 mg/m2 IV will be administered on Days 1 and 2, of each 28 day cycle. Rituximab should be administered prior to bendamustine.

Drug: IPI-145
Other Name: Duvelisib

Drug: Rituximab
Other Name: Rituxan

Drug: Bendamustine
Other Name: Treanda




Primary Outcome Measures :
  1. The number of adverse events, serious adverse events, and dose limiting toxicities as a measure of safety and tolerability [ Time Frame: up to 12 months ]
    The maximum tolerated dose of IPI-145 defined as the optimal dose at which ≤1 of 6 patients experiences a DLT assessed by NCI CTCAE v4.0.


Secondary Outcome Measures :
  1. Antitumor activity [ Time Frame: Up to 5 years ]
    Preliminary information on antitumor activity of IPI-145 when combined with rituximab, or bendamustine/rituximab as measured by objective response rate, progression free survival and overall survival data


Other Outcome Measures:
  1. PK of IPI-145 and its metabolites [ Time Frame: Day 1 ]
    Pharmacokinetics (PK) of IPI-145 and its metabolites when combined with rituximab or bendamustine/rituximab will be obtained by evaluating maximum concentration and area under the curve pre-dose and up to 6 hours post-dose.

  2. PDx of IPI-145 [ Time Frame: Up to 12 months ]
    Pharmacodynamics (PDx) of IPI-145 when combined with rituximab or bendamustine/rituximab will be evaluated by assessing chemokines and cytokines.

  3. Molecular predictors of IPI-145 [ Time Frame: Up to 12 months ]
    Develop molecular predictors of response when IPI-145 is combined with rituximab or bendamustine/rituximab by assessing protein expression and potential mutations.



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:

  1. Dose Escalation Phase

    Arm 1 and Arm 2: Limited to subjects diagnosed with low grade CD-20 positive B-Cell NHL with at least one prior anticancer treatment.

  2. Dose Expansion Phase

    Arm 1 Cohort A: Limited to subjects with CD-20 positive CLL with at least one prior anticancer treatment.

    Arm 1 Cohort B: Limited to subjects with diagnosis of CD-20 positive NHL with at least one prior anticancer treatment.

    Arm 2 Cohort A: Limited to subjects with CD-20 positive CLL with at least one prior anticancer treatment.

    Arm 2 Cohort B: Limited to subjects with diagnosis of CD-20 positive NHL with at least one prior anticancer treatment.

  3. Disease status requirement:

    • CLL subjects: symptomatic disease that mandate treatment;
    • Indolent NHL subjects: symptomatic disease requiring treatment according to the clinical judgment of the investigator;
    • Other lymphoma subjects: disease requiring treatment according to the judgment of the investigator.
  4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤2.
  5. Subject must have measurable disease using the disease-specific response criteria for NHL or CLL
  6. Age ≥ 18 years.
  7. Subject has recovered from all clinically significant toxicities related to prior antineoplastic therapies with the exception of alopecia and bone marrow and organ functions.
  8. Adequate organ system function ≤2 weeks prior to Day 1, defined as follows:

    • Absolute neutrophil count (ANC) ≥1.0 x 109/L unless related to underlying CLL or indolent NHL bone marrow involvement, and then ANC ≥500 x 109/L permitted.
    • Platelets ≥100 x 109/L unless related to underlying CLL or indolent NHL bone marrow involvement, and then platelets ≥75 x 109/L permitted.
    • Subjects receiving IPI-145 plus rituximab with bone marrow involvement may enroll with platelets ≥40 x 109/L.
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 x ULN and total bilirubin ≤1.5 times the upper limit of normal (ULN) (except for subjects with Gilbert's disease)
    • Serum creatinine ≤1.5 x ULN
  9. Life expectancy of ≥12 weeks.
  10. Women of child-bearing potential (WCBP) must have a negative serum or urine pregnancy test.
  11. Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

  1. Prior allogeneic hematopoietic stem cell transplant (HSCT).
  2. Prior autologous transplant or radioimmunotherapy ≤6 months prior to the first dose of trial treatment.
  3. Subject has a high grade lymphoma such as Burkitt's, lymphoblastic or small non-cleaved cell lymphomas. Subjects with intermediate grade lymphoma (such as diffuse large B-cell lymphoma) are eligible.
  4. Subjects with diffuse B-cell lymphoma must either not be eligible for autologous bone marrow transplant (BMT) or relapsed after autologous BMT.
  5. More than three previous cytotoxic chemotherapy regimens for subjects treated on the arm containing bendamustine.
  6. Subjects who have had a severe allergic or anaphylactic reaction to any humanized or murine monoclonal antibodies.
  7. Chemotherapy, cancer immunosuppressive therapy, growth factors (except erythropoietin), radiation therapy (other than whole brain irradiation [WBI]) surgery or ablative therapy or investigational drugs/devices ≤28 days before first dose of trial treatment.
  8. Subjects receiving high doses of corticosteroids must have been tapered to a stable dose at least 7 days before the first dose of trial treatment.
  9. Tyrosine kinase inhibitor within 7 days prior to the first dose of trial treatment.
  10. Subjects with overt leptomeningeal leukemia or central nervous system (CNS) lymphoma. Subjects must be free of CNS disease for a minimum of 2 months. Subjects with symptoms of CNS disease must have a negative diagnostic lumbar puncture prior to study enrollment.
  11. Subjects with a history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months.
  12. Baseline QTcF >480 ms. Note: This criterion does not apply to subjects with a left bundle branch block.
  13. Subjects who have had a venous thromboembolic event requiring anticoagulation and who meet any of the following criteria:

    • Have been on a stable dose of anticoagulation for <1 month.
    • Have had a Grade 2, 3 or 4 hemorrhages in the last 30 days.
    • Are experiencing continued symptoms for their venous thromboembolic event.
  14. Subjects with a history of liver disease as a result of alcohol abuse, chronic hepatitis, or other chronic liver disease (other than metastatic disease to the liver).
  15. Subjects with positive HBsAg, HBcAb or HCV are excluded.
  16. Subjects with a history of tuberculosis within the preceding two years.
  17. Prior surgery affecting drug absorption or any gastrointestinal dysfunction that could alter drug absorption.
  18. Subjects with a known hypersensitivity to bendamustine or rituximab.
  19. Presence of active infection within 72 hours of treatment. Subjects with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not included on the list of prohibited medications.
  20. Known diagnosis of human immunodeficiency virus (HIV).
  21. Concurrent administration of medications or foods that are strong or moderate inhibitors or inducers of CYP3A.
  22. Women who are pregnant or lactating.
  23. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
  24. Concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol or would impart excessive risk associated with study participation that would make it inappropriate for the subject to be enrolled.
  25. Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol.

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): NCT01871675


Locations
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United States, Colorado
The Colorado Blood Cancer Institute
Denver, Colorado, United States, 80218
United States, Florida
Florida Cancer Specialists
Sarasota, Florida, United States, 34232
United States, Oklahoma
Oklahoma University
Oklahoma City, Oklahoma, United States, 73104
United States, Tennessee
Tennessee Oncology, PLLC
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
SCRI Development Innovations, LLC
Infinity Pharmaceuticals, Inc.
Investigators
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Study Chair: Ian Flinn, M.D. SCRI

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Responsible Party: SCRI Development Innovations, LLC
ClinicalTrials.gov Identifier: NCT01871675     History of Changes
Other Study ID Numbers: SCRI HEMREF 34
First Posted: June 7, 2013    Key Record Dates
Last Update Posted: July 11, 2016
Last Verified: July 2016
Keywords provided by SCRI Development Innovations, LLC:
Lymphoma
Chronic Lymphocytic Leukemia
Non-Hodgkin Lymphoma
T-cell Lymphoma
Rituxan
Bendamustine
Hematologic Malignancy
Relapsed
Refractory
Additional relevant MeSH terms:
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Bendamustine Hydrochloride
Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, T-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action