The Combination of RP-3500 and Olaparib for the Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia with Specific Genetic Mutations

Inclusion Criteria

• Diagnosis of chronic lymphocytic leukemia (CLL) according to the National Cancer Institute (NCI)/ International Workshop on Chronic Lymphocytic Leukemia (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 5x10^9/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 kappa or lambda light chain restriction (typically dim immunoglobulin expression) * Negative fluorescence in situ hybridization (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 Clinical Laboratory Improvement Amendments (CLIA) certified laboratory after progression is noted from most recent line of therapy and within 6 months of screening. Primary CLL cells must harbor at least 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 and relapsed disease after 2 prior lines of therapy with no other approved therapies that are expected to have sustained therapeutic benefit
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
• Expected life expectancy of at least 12 months per the investigator
• Absolute neutrophil count >= 1000/uL (granulocyte colony-stimulating factor [G-CSF] support is allowed) unless documented bone marrow involvement of CLL (obtained =< 42 days prior to enrollment)
• Platelets of >= 50K/uL unless documented bone marrow involvement of CLL (obtained =< 42 days prior to enrollment)
• Creatinine clearance (CrCl) >= 45 mL/minute as measured by a 24 hour urine collection or calculated by the Cockcroft-Gault formula (obtained =< 42 days prior to enrollment)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) unless due to Gilbert’s disease (obtained =< 42 days prior to enrollment). For those patients with previous history of Gilbert’s disease, a direct bilirubin should be performed and must be < 1.5mg/dL
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate transaminase [AST])/serum glutamate pyruvate transaminase (SGPT) (alanine transferase [ALT]) =< 3.0 x the institutional ULN (obtained =< 42 days prior to enrollment)
• Corrected QT interval by Fredericia (QTcF) =< 470 msec (obtained =< 42 days prior to enrollment) * 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 (obtained =< 42 days prior to enrollment)
• 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 polymerase chain reaction [PCR] positive) must take lamivudine or equivalent drug during study therapy and for one year after completion of all therapy. Patients on intravenous immunoglobulin (IVIG) who are core antibody-positive but PCR negative are not mandated to take prophylaxis
• Patients who are human immunodeficiency virus (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. If current medications do interact, patients should receive alternative ART
• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 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 beta-human chorionic gonadotropin (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 beta-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 coronavirus disease 2019 (COVID-19) under the Food and Drug Administration (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 B-cell receptor (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 * Strong CYP3A inhibitors or inducers, p-glycoprotein inhibitors, or breast cancer resistance protein (BCRP) inhibitors within five half-lives or 14 days of registration, whichever is shorter
• Prior ATR inhibitor use, but prior PARP inhibitor use for any reason is allowed on study
• Major surgery 4 weeks prior to cycle 1 day 1 (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. Steroid premedications to prevent iodine contrast allergy for computed tomography (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 interstitial lung disease (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