Phase 1/1b Study of the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Clinical Activity of RP-6306 Alone or in Combination With RP-3500 or Debio 0123 in Patients With Advanced Solid Tumors
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Study Summary
To evaluate RP-6306 in patients with cancer. To evaluate the assessment of safety, tolerability, dose and schedule (including the recommended Phase 2 dose). To assess the safety and tolerability of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123 in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD) and assess preliminary anti-tumor activity. Evaluate the safety profile and MTD of RP-6306 alone and in combination with RP-3500 or in combination with Debio 0123 when administered orally to establish the recommended Phase 2 dose and schedule Characterize the PK and pharmacodynamics of RP-6306 alone and in combination with RP- 3500 or in combination with Debio 0123 Assess preliminary anti-tumor activity associated with RP-6306 alone and in combination with RP- 3500 or in combination with Debio 0123 Endpoints: safety, tolerability, RP2D, preliminary efficacy (RECIST v1.1, GCIG CA-125), clinical benefit rate (CBR; RECIST/GCIG CA-125 or therapy duration ≥16w), ctDNA molecular response, PK and PD. To evaluate lunresertib in combination with Debio 0123, a highly selective, brain-penetrant, clinical WEE1 inhibitor, in Module 4 of the ongoing MYTHIC trial in patients with advanced solid tumors harboring CCNE1 amplification or FBXW7 or PPP2R1A deleterious alterations. Dose expansion: To evaluate lunresertib in combination with camonsertib in patients with ovarian and endometrial cancers To evaluate dose expansion clinical trial of lunresertib and camonsertib at the recommended Phase 2 dose (RP2D) in patients with platinum-resistant ovarian and endometrial cancers harboring CCNE1 amplification or FBXW7 or PPP2R1A mutations To analyse factors associated with anaemia risk and implemented pt specific schedule and modification strategies (dose or schedule) to optimise tolerability. Exposure response (E-R) analysis assessed daily PK exposures at steady state (AUC and Cmax) vs. the probability of anaemia. Cox regression models assessed baseline (BL) predictive factors of Gr3 anaemia in pts at RP2D range. Overall rates and exposure-adjusted event rate (Gr3 events/pt-month of observation) of anaemia were analysed to assess the impact of the schedule optimisation approach. Anti-tumour activity was assessed radiographically (RECISTv1.1) and by exploratory circulating markers. Endpoints were response rate (RECISTv1.1 unconfirmed+confirmed), clinical benefit rate (CBR; response per RECISTv1.1 or treatment for ≥16w w/o PD), progression-free survival (PFS), and molecular response rate (MRR; ≥50% decline in circulating tumor DNA). Target and pathway engagement were evaluated by IHC in paired tumor biopsies.
Objectives included safety, tolerability, recommended doses (RD), pharmacokinetics (PK), pharmacodynamics (PDy), antitumor activity and molecular response rate (MRR; ≥50% decline in circulating tumor DNA).
- Male or female and ≥12 years-of-age at the time of informed consent. Lansky performance status ≥50% for patients ≤16 years of age, or ECOG score of 0, 1, (or 2 for module 1) for patients >16 years of age. Locally advanced or metastatic resistant or refractory solid tumors. Patients <18 years of age must weigh at least 40 kg. Submission of available tumor tissue at screening or willingness to have a biopsy performed if safe and feasible Next generation sequencing (NGS) report obtained in a CLIA-certified or equivalent laboratory demonstrating eligible tumor biomarker. CCNE1 amplification (non-equivocal) as determined by either a tumor or plasma NGS test, or FISH FBXW7 deleterious mutations identified by either a tumor or plasma NGS test PPP2R1A deleterious mutations identified by either a tumor or plasma NGS test Measurable disease as per RECIST v1.1. For certain modules, patients with prostate cancer or ovarian cancer that have non-measurable disease but have elevated tumor markers (PSA or CA-125, respectively) can also be eligible Ability to swallow and retain oral medications. Acceptable hematologic and organ function at screening. Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening. Resolution of all toxicities of prior therapy or surgical procedures. Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment. Written informed consent and assent, according to local guidelines, signed and dated by the participating patient or legal guardian prior to the performance of any study-specific procedures, sampling, or analyses. Male or female and >or= 12 years-of-age at the time of signature of the informed consent form (ICF). Lansky performance status =50% for patients =16 years of age, or ECOG score of 0, 1, or 2 for patients >16 years of age. All patients must have locally advanced or metastatic resistant or refractory solid tumors. Patients <18 years-of-age will be eligible only if standard or available curative therapy does not exist. Patients >or= 18 years-of-age are eligible if, in the opinion of the investigator, the patient is not a candidate for, or would be unlikely to tolerate or derive significant clinical benefit from, appropriate standard-of-care therapy, or if the patient declines standard-of-care therapy. Patients <18 years of age must weigh at least 40 kg. Archived tumor tissue sample available or lesion that can be safely biopsied if the archival sample is not available. All patient’s tumors, except for types of endometrial cancer listed in criteria #8, must have evidence of at least one of the following as reported by a local CLIA-certified or equivalent (ex-United States [US]) laboratory and centrally confirmed by PODS: a. CCNE1 amplification (non-equivocal) as determined by either a tumor or plasma NGS test, or FISH b. FBXW7 deleterious mutations identified by either a tumor or plasma NGS test c. Proprietary gene deleterious mutations identified by either a tumor or plasma NGS test d. For backfill cohorts, tumors with other genes with mechanistic rationale agreed upon between the Sponsor and Investigator will be accepted. The following types of endometrial cancer are eligible (for Module 1 only): a. Serous endometrial cancer (p53 IHC must be confirmed to be aberrant or local NGS report confirming TP53 loss of function mutation must be provided) b. Carcinosarcoma of the endometrium c. Grade 3 endometrioid and undifferentiated carcinoma (p53 IHC must be confirmed to be aberrant or local NGS report confirming TP53 loss of function mutation must be provided; MMR IHC must be retained and/or tumor must be MSS; polymerase epsilon (POLE) hypermutated type must be excluded) Measurable disease as per RECIST v1.1. Ability to comply with the protocol and study procedures detailed in the Schedule of Assessments. Ability to swallow and retain oral medications. Acceptable organ function at Screening, as evidenced by the following laboratory data: a. Serum creatinine or= 2.5 g/dL d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) or= 9.0 g/dL c. ANC >or=1500 cells/mm^3 d. Platelet count >or= 100,000 cells/mm^3 Negative pregnancy test (serum) for women of childbearing potential at Screening.Male patients with female partners of childbearing potential must follow a contraception method (oral contraceptives allowed) during their participation in the study for 4 months following last dose of drug. Male patients must also refrain from donating sperm during their participation in the study and for 4 months following last dose of study drug. Resolution of all toxicities of prior therapy or surgical procedures to baseline or Grade 1 (except for neuropathy, hypothyroidism requiring medication, and alopecia, which must have resolved to Grade or= 12 weeks after the start of the treatment according to the investigator’s judgment. Additional Inclusion Criteria for Module 1c: Ability to consume a high-fat meal and fast for 12 hours. Module 1c will only be open to patients =18 years-of-age.
- Advanced solid tumors with CCNE1 amplification (amp), or FBXW7 or PPP2R1A deleterious mutations (mut) were treated with zedo (daily dosing) plus lunre (3 days on/4 days off)
- Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, whichever is shorter, prior to first dose of study drug.
- History or current condition, therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment.
- Patients who are pregnant or breastfeeding.
- Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the participating patient's safety.
- Major surgery within 4 weeks prior to first dose of RP-6306.
- Uncontrolled, symptomatic brain metastases.
- Uncontrolled hypertension.
- Certain prior anti-cancer therapy
- Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.
- Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, whichever is shorter, prior to first dose of study drug. For drugs for which 5 half-lives is
- History or current condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results, or interfere with the patient’s participation for the full duration of the study treatment.
- Patients who are pregnant or breastfeeding.
- Known sensitivity to any of the ingredients of the RP-6306.
- Patient who are unable to swallow oral medications.
- Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction (such as ascites, coagulopathy, or encephalopathy), or other reasons which, in the investigator’s opinion, could compromise the participating patient’s safety, or interfere with or compromise the integrity of the study outcomes.
- Major surgery (excluding placement of vascular access) within 4 weeks prior to first dose of RP-6306.
- Uncontrolled, symptomatic brain metastases. Patients with previously treated brain metastases may participate provided the metastases are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms are controlled and stable), have no evidence of new or enlarged brain metastases, and are clinically stable and off steroids for at least 7 days prior to study drug.
- Uncontrolled hypertension (systolic blood pressure [BP] >or=160 mmHg; diastolic BP >or= 100 mmHg) despite adequate treatment prior to first dose of RP-6306.
- Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness. In equivocal cases, patients whose viral load is negative, may be eligible. HIV seropositive patients who are healthy and low risk for AIDSrelated outcomes could be considered eligible. Eligibility criteria for HIV positive patients should be evaluated and discussed with the sponsor’s medical monitor and will be based on current and past CD4 and T-cell counts, history (if any) of AIDS defining conditions (e.g., opportunistic infections), and status of HIV treatment
- Moderate or severe hepatic impairment (i.e., Child-Pugh class B or C).
- Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) >or= Class 2:
- a. Unstable angina pectoris
- b. Congestive heart failure
- c. Acute myocardial infarction
- d. Conduction abnormality not controlled with pacemaker or medication
- e. Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
- f. Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long ECG interval measured from the onset of the QRS complex to the end of the T wave (QT) syndrome
- Mean resting QT interval corrected for heart rate (QTc) interval using the Fridericia formula (QTcF) >450 msec/male and >470 msec/female (as calculated per institutional standards) obtained from 3 ECGs 2-5 minutes apart at study entry.
- Current treatment with medications that are well-known to prolong the QT interval.
- Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.
- Patients who are receiving strong CYP3A inhibitors or inducers within 14 days prior to first dose of study drug.
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