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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Chronic Lymphocytic Leukemia; Non-Hodgkin Lymphoma; T-cell Lymphoma
• Intervention / Treatment: Drug: Rituximab; Drug: Bendamustine; Drug: IPI-145

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

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • The Colorado Blood Cancer Institute
  • Florida
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology, PLLC

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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: Rituximab; Other Names: Rituxan; Drug: IPI-145; Other Names: Duvelisib
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: Rituximab; Other Names: Rituxan; Drug: Bendamustine; Other Names: Treanda; Drug: IPI-145; Other Names: Duvelisib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of adverse events, serious adverse events, and dose limiting toxicities as a measure of safety and tolerability	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.	up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antitumor activity	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	Up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK of IPI-145 and its metabolites	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.	Day 1
PDx of IPI-145	Pharmacodynamics (PDx) of IPI-145 when combined with rituximab or bendamustine/rituximab will be evaluated by assessing chemokines and cytokines.	Up to 12 months
Molecular predictors of IPI-145	Develop molecular predictors of response when IPI-145 is combined with rituximab or bendamustine/rituximab by assessing protein expression and potential mutations.	Up to 12 months

Collaborators and Investigators

• Sponsor: SCRI Development Innovations, LLC
• Collaborators: Infinity Pharmaceuticals, Inc.
• Investigators: Study Chair: Ian Flinn, M.D., SCRI

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: May 31, 2013
• First Submitted That Met QC Criteria: June 4, 2013
• First Posted (Estimate): June 7, 2013

Study Record Updates

• Last Update Posted (Estimate): July 11, 2016
• Last Update Submitted That Met QC Criteria: July 7, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Lymphoma; Relapsed; Refractory; Rituxan; Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Hematologic Malignancy; Bendamustine; T-cell Lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Lymphoma; Leukemia; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Bendamustine Hydrochloride; Rituximab
• Other Study ID Numbers: SCRI HEMREF 34