A Phase 1b/2 Study of IPI-145 Plus FCR in Previously Untr... | NCT02158091

NCT02158091

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Secura Bio, Inc.	INDUSTRY

Oversight Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
IPI-145	Experimental	Phase I-Dose escalation will occur using a standard 3-3 dose escalation beginning in dose level 1 with dose cohorts and escalation. Each treatment cycle lasts 28 days (except cycle 1, which is 35 days) during which time IPI-145 will be taken twice daily. The study begins with 1 week of IPI-145 monotherapy. Fludarabine, cyclophosphamide, rituximab (iFCR) - FCR will subsequently be introduced after 1 week and administered at standard dosing for up to 6 cycles, with dose reductions permitted. IPI-145 will be continued through the course of chemotherapy and for up to 2 years maintenance after completing chemotherapy Phase II - 20 additional patients treated with IPI-145 at the Recommended Phase II Dose (RP2D) + fludarabine, cyclophosphamide, rituximab (FCR) with standard dosing.	Drug: IPI-145 Drug: Fludarabine Drug: Cyclophosphamide Drug: Rituximab

Name	Type	Description	Arm Group Labels	Other Names
IPI-145	Drug	oral PI3K delta/gamma inhibitor	IPI-145
Fludarabine

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I	To assess the safety of IPI145 in combination with FCR in previously untreated younger patients with CLL. DLT is based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. DLT refers to toxicities experienced at any time during the study treatment, defined as Grade 3 or greater hematologic toxicity (except Grade 3 or Grade 4 neutropenia or thrombocytopenia that lasts less than or equal to 10 days off treatment), any Grade 3 or greater non-hematologic toxicity (except Grade 3 or greater nausea, vomiting, diarrhea, Grade 3 infusion reactions), Grade 3 asymptomatic laboratory abnormalities that improve to grade 2 or less within 3 days, Inability to receive day 1 therapy of Cycle 2 even after a three week treatment delay due to drug related toxicity from prior cycle, and any Grade 4 or greater elevation in AST ALT values	. Participants were assessed every week or more often as needed during Cycle 1, and every Day 1 Cycles 2 and onward-Dose-limiting toxicities (DLTs) occurring during the first cycle of treatment will be used in determining the Phase II MTD/RP2D
Number of Patients Who Had a Minimal Residual Disease (MRD) Negative Complete Response (CR) 2 Months After Chemotherapy	To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 2 months post last cycle of FCR, participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (IPI-145+ FCR) in tandem with a chest,neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. This will include all patients treated and evaluable at maximum tolerated dose, and at the recommended phase II dose ( RP2D)	2 months after completion of combination therapy of IPI-145 and FCR

Secondary Outcomes

Measure	Description	Time Frame
Overall Response Rate	Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)	At baseline, End of Cycle 3, and 2 months post FCR
Number of Participants With Serious and Non-Serious Adverse Events

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

confirmed diagnosis of CLL and an indication for treatment as per IW-CLL 2008 criteria
no prior therapy for CLL
age 18-65 -- ECOG performance status ≤1

Exclusion Criteria:

May not be receiving any other study agents
Known CNS involvement
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 women are excluded from this study because IPI-145 has the potential for teratogenic or abortifacient effects.
Individuals with a history of a different malignancy are ineligible except for the following circumstances. disease-free for at least 5 years and deemed to be at low risk for recurrence. Individuals with the following cancers are eligible if diagnosed and treated with curative intent within the past 5 years: cervical cancer in situ, localized prostate cancer, and basal cell or squamous cell carcinoma of the skin
HIV-positive individuals, because of the potential for pharmacokinetic interactions with IPI-145
Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN); direct bilirubin >1.5 x ULN, unless due to hemolysis or Gilbert's syndrome
Inadequate renal function defined by serum creatinine >1.5 x ULN.
Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left bundle branch block
Concurrent treatment with any agent known to prolong the QTc interval
Patients with a history of active tuberculosis within the preceding two years.
Patients who have had a venous thromboembolic event (e.g., PE/DVT) 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 hemorrhage in the last 30 days
Are experiencing continued symptoms from their event
History of alcohol abuse, chronic hepatitis, or other chronic liver disease (other than direct CLL liver involvement)
Foods or medications that are strong or moderate inhibitors or inducers of CYP3A taken within 1 week prior to study treatment and for the duration of the study
Unable to receive prophylactic treatment for pneumocystis

Name	Affiliation	Role
Matthew Davids, MD	Dana-Farber Cancer Institute	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Beth Isreal Deaconess Medical Center		Boston	Massachusetts	02115	United States
Dana Farber Cancer Institute

Arm/Group Information

ID	Title	Description
FG000	Phase I Cohort 1: IPI-145 25mg Once Daily + FCR	Phase I Cohort 1 patients received oral agent IPI-145 25mg daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities.
FG001	Phase I Cohort 2 (MTD): IPI-145 25mg Twice Daily + FCR	Phase I Cohort 2 patients received oral agent IPI-145 25mg twice daily ( BID)on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities.
FG002	Phase II Dose Expansion(RP2D)-IPI-145 25mg Twice Daily + FCR	Phase II (MTD)CLL participants received the regimen established in the Phase I study ( January 2015). Phase II Participants received oral IPI-145 25mg twice daily (BID) for up to 6 cycles of combination therapy and 2 years of maintenance ( monotherapy) and received standard dosing if Fludarabine, Cyclophosphamide, and Rituxan (FCR) on days 1-3 of each cycle for up to 6 cycles. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Phase I Cohort 1: IPI-145 25mg Once Daily + FCR	Phase I Cohort 1 patients received oral agent IPI-145 25mg daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I	To assess the safety of IPI145 in combination with FCR in previously untreated younger patients with CLL. DLT is based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. DLT refers to toxicities experienced at any time during the study treatment, defined as Grade 3 or greater hematologic toxicity (except Grade 3 or Grade 4 neutropenia or thrombocytopenia that lasts less than or equal to 10 days off treatment), any Grade 3 or greater non-hematologic toxicity (except Grade 3 or greater nausea, vomiting, diarrhea, Grade 3 infusion reactions), Grade 3 asymptomatic laboratory abnormalities that improve to grade 2 or less within 3 days, Inability to receive day 1 therapy of Cycle 2 even after a three week treatment delay due to drug related toxicity from prior cycle, and any Grade 4 or greater elevation in AST ALT values	Patients who have received no prior therapy for CLL but who meet IW-CLL 2008 Criteria for requiring treatment	Posted		Count of Participants		Participants		. Participants were assessed every week or more often as needed during Cycle 1, and every Day 1 Cycles 2 and onward-Dose-limiting toxicities (DLTs) occurring during the first cycle of treatment will be used in determining the Phase II MTD/RP2D

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Phase 1 Cohort 1: IPI-145 25mg Once Daily + FCR	Phase I Cohort 1 patients received oral agent IPI-145 25mg daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities.

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Febrile neutropenia	Blood and lymphatic system disorders	CTCAE (4.0)	Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Abdominal pain	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment

Title	Organization	Phone	Extension	Email
Matthew Davids, MD	Dana-Farber Cancer Institute	617-632-6331		matthew_davids@dfci.harvard.edu

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Mar 28, 2017	Sep 11, 2018	Prot_SAP_000.pdf

ID	Term
D015451	Leukemia, Lymphocytic, Chronic, B-Cell

ID	Term
D015448	Leukemia, B-Cell
D007945	Leukemia, Lymphoid
D007938	Leukemia
D009370	Neoplasms by Histologic Type

ID	Term
C586691	duvelisib
C024352	fludarabine
C042382	fludarabine phosphate
D003520	Cyclophosphamide
D000069283	Rituximab

ID	Term
D010752	Phosphoramide Mustards
D009588	Nitrogen Mustard Compounds
D009150	Mustard Compounds
D006846	Hydrocarbons, Halogenated

ID	Title	Description
OG000	Phase I Cohort 1: IPI-145 25mg Once Daily + FCR	Phase I Cohort 1 patients received oral agent IPI-145 25mg daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities.
OG001	Phase I Cohort 2 (MTD): IPI-145 25mg Twice Daily + FCR	Phase I Cohort 2 patients received oral agent IPI-145 25mg twice daily ( BID)on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities.