RP-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refractory Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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This is an open-label, multicenter, phase Ib/II study of the combination of RP-3500 and olaparib in R/R CLL patients with DDR deficiencies.

Detailed Description
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The Phase Ib part of the trial will seek to assess the MTD of RP-3500 in combination with olaparib. Given the potential overlapping toxicities of RP-3500 and olaparib, a keyboard phase I design, a novel Bayesian method that typically underestimates the MTD,61 will be employed. The target toxicity is 30% with an equivalence interval between 25-33% of patients. With an anticipated 3 dose levels (DL) and an option for a DL-1, up to 18 patients may be required to determine the MTD. A maximum of 12 patients will be treated at a DL. After completion of the phase Ib portion and assignment of the RP2D, continuous enrollment of patients may commence into the phase II dose expansion portion. All patients enrolled at the RP2D during the phase Ib dose-escalation portion of the trial can be carried over into the phase II analysis. The maximum number of patients that can be carried over from the dose escalation to the dose-expansion portion is 12. The phase II dose expansion will consist of two separate cohorts of subjects: an enrichment cohort and a cohort for all other eligible subjects. All subjects enrolled into the enrichment cohort must have a del(11q) and/or ATM mutation. Eight subjects will be enrolled into the enrichment cohort and 16 will be enrolled into the second cohort for a total phase II cohort of 24 patients.

Official Title
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A Phase Ib/II Trial of Combination RP-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refractory Chronic Lymphocytic Leukemia

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: RP-3500 in combination with Olaparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of CLL according to the NCI/IWCLL criteria. --This includes previous documentation of: Biopsy-proven small lymphocytic lymphoma OR Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following: Peripheral blood monoclonal B cell population of greater than 5x109/L Immunophenotype consistent with CLL defined as: The predominant population of lymphocytes share both B cell antigens [CD19, CD20 (typically dim expression), or CD23] as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc). Clonality as evidenced by κ or λ light chain restriction (typically dim immunoglobulin expression) Negative FISH analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g. marrow aspirate), or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy (e.g. marrow aspirate or lymph node biopsy). Repeat testing of somatic mutations and FISH analysis must be performed by a CLIA certified laboratory after progression is noted from most recent line of therapy and within 6 months of screening. Primary CLL cells must harbor one of these abnormalities: Somatic gene mutation testing shows mutation(s) in TP53, ATM, SF3B1, XPO1 and/or POT1 Cytogenetic FISH analysis shows deletion 17p13 and/or deletion 11q22.3 Relapsed or refractory after at least 2 prior lines of therapy, and in the opinion of the treating Investigator are either not eligible for other approved therapies or no approved therapies are expected to have sustained therapeutic benefit. Patient in need of treatment or change in treatment per iwCLL criteria. --Patients on BTK, PI3K or BCL2 inhibitors may enroll without meeting iwCLL criteria for treatment as long as there is clinical evidence of progression (i.e. increasing lymphocytosis, worsening anemia/thrombocytopenia attributable to CLL disease progression, increasing lymphadenopathy, or worsening patient symptoms) and require change in treatment at the discretion of the treating provider. Patients must still meet all other inclusion/exclusion criteria for enrollment including appropriate washout periods (5.2.2) and relapsed disease after 2 prior lines of therapy with no other approved therapies that are expected to have sustained therapeutic benefit (5.1.3). Age ≥18 years ECOG performance status between 0-2 Expected life expectancy of at least 12 months per the investigator. The following laboratory or clinical values obtained ≤ 42 days prior to enrollment: Absolute neutrophil count ≥1000/µL (G-CSF support is allowed) unless documented bone marrow involvement of CLL Platelets of ≥50K/µL unless documented bone marrow involvement of CLL Creatinine Clearance (CrCl) ≥45 mL/minute as measured by a 24 hour urine collection or calculated by the Cockcroft-Gault Formula Total bilirubin ≤ 1.5 x institutional ULN unless due to Gilbert's disease. For those patients with previous history of Gilbert's disease, a direct bilirubin should be performed and must be <1.5mg/dL. SGOT (AST)/SGPT (ALT) ≤3.0 x the institutional ULN QTcF ≤470 msec For patients with prolonged AT interval due to bundle branch block, a corrected value ≤470 msec and confirmation by cardiologist that patient is asymptomatic and that no other cardiac conduction or cardiac abnormality is present would pose any safety issues for the patient. Recommended correction of QT for patients with bundle branch block are as follows: Patient's QRS is 160 msec, and the measured QT is 510 msec. As the normal QRS is  120 msec, subtract 120 msec from the measured QRS of the patient (160-120 = 40 msec) and then subtract this result from the measured QT (510-40=470 msec). Pulse oximetry reading of ≥90% on room air Able to adhere to study visit schedule and other protocol requirements Patients must be able to swallow capsules Patients must be able to receive xanthine oxidase inhibitor and/or rasburicase for tumor lysis syndrome prophylaxis. Patients with a history of hepatitis B (surface antigen or core antibody-positive and PCR positive) must take lamivudine or equivalent drug during study therapy and for one year after completion of all therapy. Patients on IVIG who are core antibody-positive but PCR negative are not mandated to take prophylaxis. Patients who are HIV+ are eligible under the following circumstances: Undetectable HIV viral load (laboratory value obtained within the last 6 months prior to enrollment) CD4 count ≥200 (laboratory value obtained within the last 6 months prior to enrollment) Actively taking antiretroviral therapy (ART) Current ART therapy cannot have significant interactions with RP-3500 or Olaparib (Refer to Appendix 5). If current medications do interact, patients should receive alternative ART. Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior cancer therapy, unless considered clinically not significant by the treating investigator. Female patients capable of reproduction or males who have partners capable of reproduction must agree to the use of an effective contraceptive method during the course of the study and for 6 months following the completion of their last treatment. Females of childbearing potential must have a negative serum β-Hcg pregnancy test result within 3 days of the first study dose. Female patients who are surgically sterilized or who are >45 years old and have not experienced menses for >2 years may have β-Hcg pregnancy test waived. Exclusion Criteria: Patients who are currently receiving any other investigational drug. Patients who are or have received therapies for the prevention, treatment or management of COVID-19 under the FDA emergency use authorization are allowed to enroll. Patients who have received: Radiation or chemotherapy ≤2 weeks prior to registration. Immunotherapy or targeted therapy ≤2 weeks prior to registration. ---Patients currently on BCR pathway antagonists (i.e. BTK and PI3K inhibitors, etc) require a 2 day wash out period prior to starting combination therapy with RP-3500 and olaparib as these subjects progress quickly after treatment discontinuation. Moderate/strong CYP3A inhibitors or inducers, strong CYP2C8 inhibitors, moderate CYP2C inducers, p-glycoprotein inhibitors, or BCRP inhibitors within five half-lives or 14 days of registration, whichever is shorter (See Appendix 5). Prior ATR inhibitor use, but prior PARP inhibitor use for any reason is allowed on study. Major surgery 4 weeks prior to C1D1 or who have not fully recovered from major surgery. Evidence of active Richter's Transformation Disease states requiring steroids (e.g. adrenal insufficiency, autoimmune conditions) are allowed as long as the steroid dose is ≤10mg of prednisone or equivalent dose of another steroid. Steroids premedications to prevent iodine contrast allergy for CT scans are allowed. Patients who have undergone autologous stem cell transplant ≤4 weeks or allogeneic stem cell transplant ≤12 weeks prior to cycle 1 day 1 or have active graft-versus-host disease are excluded. Patients who have active, clinically significant hepatic impairment (≥ moderate hepatic impairment according to the NCI/Child-Pugh classification) Prior history of another malignancy except for the following: Patients with current history of basal or squamous skin carcinoma, cervical carcinoma in situ, localized breast cancer requiring hormonal therapy, or localized prostate cancer (Gleason score <6) are allowed. Previously treated malignancies (with chemotherapy, radiation, and/or surgery) currently deemed to have been in complete remission for at least 24 months. Patients with active known central nervous system (CNS) involvement of CLL. Patients with a history of CNS CLL now in remission are eligible for the trial. Patients with uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, extensive bilateral interstitial lung disease, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements. --Patients with a history of pneumonitis or pulmonary disease that could predispose them to development of ILD and/or underlying respiratory conditions should be excluded. Known prior severe hypersensitivity to RP-3500, olaparib, or any component in its formulations (NCI CTCAE v5.0 Grade ≥ 3). Female patients who are pregnant or actively breast feeding Patients with conditions significantly affecting gastrointestinal function including, but not limited to: Significant resection of the stomach or small bowel Symptomatic inflammatory bowel disease Partial or complete bowel obstruction

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ib: Dose Escalation<br>To assess the MTD of RP-3500 in combination with olaparib | Drug: RP-3500 in combination with Olaparib<br>* During dose escalation, four DLs of combination therapy of RP-3500 and olaparib may be explored. Subjects will be enrolled in cohorts of three starting with DL 1. Enrollment will be placed on hold to allow for all members of a cohort to complete the Dose Limiting Toxicity (DLT) period. Once all subjects in a cohort have completed the defined DLT evaluation period, the assignment of the dose level for the following cohort will be made per the decision algorithm. Once RP2D is assigned continuous enrollment will begin among the 2 expansion cohorts.<br>|
| Experimental: Phase II: Dose Expansion Enrichment Cohort<br>All subjects enrolled into the enrichment cohort must have a del(11q) and/or ATM mutation | Drug: RP-3500 in combination with Olaparib<br>* During dose escalation, four DLs of combination therapy of RP-3500 and olaparib may be explored. Subjects will be enrolled in cohorts of three starting with DL 1. Enrollment will be placed on hold to allow for all members of a cohort to complete the Dose Limiting Toxicity (DLT) period. Once all subjects in a cohort have completed the defined DLT evaluation period, the assignment of the dose level for the following cohort will be made per the decision algorithm. Once RP2D is assigned continuous enrollment will begin among the 2 expansion cohorts.<br>|
| Experimental: Phase II: Dose Expansion Eligible Subjects Cohort<br>Cohort will include all other eligible subjects for Dose Expansion. | Drug: RP-3500 in combination with Olaparib<br>* During dose escalation, four DLs of combination therapy of RP-3500 and olaparib may be explored. Subjects will be enrolled in cohorts of three starting with DL 1. Enrollment will be placed on hold to allow for all members of a cohort to complete the Dose Limiting Toxicity (DLT) period. Once all subjects in a cohort have completed the defined DLT evaluation period, the assignment of the dose level for the following cohort will be made per the decision algorithm. Once RP2D is assigned continuous enrollment will begin among the 2 expansion cohorts.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of dose-limiting toxicities (DLTs) during the DLT evaluation period | assess the maximum tolerated dose (MTD) and determine the recommended phase 2 dose (RP2D) | 28 days | 
| Overall response rate (ORR) | Assess the overall response rate (ORR) of combination RP-3500 and olaparib. Overall response rate (ORR) will be defined by the proportion of subjects achieving any confirmed partial (PR) and complete response (CR) as assessed by 2018 International Working Group on Chronic Lymphocytic Leukemia (iwCLL) response criteria. | up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by type, severity (as defined by the NIH CTCAE, version 5.0), seriousness, duration, and relationship to study treatment | assess the safety and tolerability of RP-3500 and olaparib | up to 1 year | 
| Progression-free survival (PFS) as defined as the time from study drug initiation to the time documented disease progression (as assessed by 2018 iwCLL criteria) or death from any cause | To assess progression-free survival (PFS) | up to 10 years | 
| OS as defined as the time from registration until death from any cause | To assess overall survival (OS) | up to 10 years | 
| DoR as defined as the interval of time from the date of initial documented response (PR or better as per 2018 iwCLL criteria for response) to the time of progression | To assess the duration of response (DoR | up to 10 years |