PLX038 (PEGylated SN38) and Rucaparib in Solid Tumors and Small Cell Cancers

Study Overview
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Brief Summary
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Background: Drugs known as PARP inhibitors are known to help stop tumor growth in patients with breast, ovarian cancers and many other cancers including prostate and pancreatic cancers. Many research studies done in animals and human cells have shown that these type of drugs can improve how well chemotherapy works. Standard chemotherapy can be too toxic to be combined with PARP inhibitors. In this study, we use a new form of chemotherapy called PLX038 to see if it can be safely combined with PARP inhibitors to shrink tumors. Objective: To find a safe combination of PLX038 and rucaparib, and to see if this mix will cause tumors to shrink. Eligibility: People age 18 and older with solid tumors, SCLC, or small cell cancer outside their lungs. Design: Participants will be screened with: Physical exam Blood tests Records of their diagnosis (or they will have a tumor biopsy) A review of their symptoms and medications A review of their ability to perform their normal activities Electrocardiograms to measure the electrical activity of the heart Computed tomography (CT) scans of the chest, abdomen, and pelvis. CT scans are a series of X-rays. Participants will get PLX038 by intravenous catheter on Day 1 of each cycle (1 cycle = 21 days). For this, a small plastic tube is put into an arm vein. They will take rucaparib twice daily by mouth on Days 3 to 19 of each cycle. They will keep a medicine diary. Participants may give a hair sample. They may have optional tumor biopsies. Screening tests are repeated throughout the study. About 30 days after treatment ends, participants will have a safety follow-up visit. They will give blood samples, talk about their health, and get a physical exam. Then they will be called or emailed every 6 months....

Detailed Description
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Background: We hypothesize that a dose-escalation strategy that incorporates tumor targeted DNA-damaging chemotherapy and DNA-damage response (DDR) inhibitors could allow safe and effective administration of DDR inhibitor-chemotherapy combination. PLX038 is a PEGylated conjugate of SN38 with improved properties including increased solubility, higher exposure and longer half-life. SN-38 is the active metabolite of CPT-11 (irinotecan) that inhibits topoisomerase 1 (Top1) and causes DNA strand breakage. As a specific DNA damaging agent, SN-38 enhances cell kill in tumors deficient in the DNA-damage response and when combined with inhibitors of the DDR. Rucaparib is a potent oral poly ADP ribose polymerase (PARP) inhibitor that is approved for the maintenance treatment of participants with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. We hypothesize that the combination of PLX038 plus rucaparib is more efficacious than either agent alone. Objectives: Phase I: To identify the maximum tolerated dose (MTD) of PLX038 in combination with rucaparib. Phase II: To assess the efficacy with respect to clinical benefit rate (CBR) (CR+PR+SD) for 4 months according to Response Evaluation Criteria (RECIST 1.1) of a combination of PLX038 and rucaparib in participants with small cell lung cancer and extra-pulmonary small cell carcinomas. Eligibility: Subjects with histologically confirmed solid tumors (Phase I) OR histologically or cytologically confirmed small cell lung cancer (SCLC) (Phase II) OR histologically or cytologically confirmed extra-pulmonary small cell carcinomas (Phase II). Age greater than or equal to 18 years Subjects must have evaluable or measurable disease. ECOG performance status less than or equal to 2 Adequate organ function Design: This is an open label Phase I/II trial accruing initially one cohort to determine maximum tolerated dose (MTD) of combined treatment of PLX038 and rucaparib (Phase I); and to examine the safety and efficacy of PLX038 in combination with rucaparib in the following cohort (Phase II). PLX038 will be administered by IV infusion on day 1 of every 21-days cycle, rucaparib will be administered PO twice daily on days 6 to 19 of every cycle. Treatment will continue until progression or unacceptable toxicity. Biomarkers of participant response to treatment will be investigated in an exploratory manner pre and post-treatment.

Official Title
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Phase I/II Trial of PLX038 (PEGylated SN38) and Rucaparib in Solid Tumors and Small Cell Cancers

Conditions
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Small Cell Lung Cancer, Extra-Pulmonary Small Cell Carcinomas

Intervention / Treatment
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* Drug: PLX038
* Drug: Rucaparib


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Subjects with: histologically confirmed solid tumors (Phase I), OR histologically or cytologically confirmed SCLC (Phase II), OR histologically or cytologically confirmed extra-pulmonary small cell carcinomas (Phase II). Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of PLX038 in combination with rucaparib in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. Subjects must have progressed on or after standard first-line systemic chemotherapy and have no effective treatment options. Participants must have disease that is not amenable to potentially curative resection. Participants must have measurable disease per RECIST 1.1. Participants with asymptomatic brain metastases and treated brain metastases are eligible. ECOG performance status less than or equal to 2. Adequate hematological function defined by: white blood cell (WBC) count greater than or equal to 3 x 10^9/L, absolute neutrophil count (ANC) greater than or equal to 1.5 x10^9/L, platelet count greater than or equal to 100 x 10^9/L, Hgb greater than or equal to 9 g/ dL Adequate hepatic function defined by: a total bilirubin level less than or equal to 1.5 x ULN, an AST level less than or equal to 2.5xULN, (less than or equal to 5X ULN if liver metastasis) an ALT level less than or equal to 2.5 xULN, (less than or equal to 5X ULN if liver metastasis). Adequate renal function defined by: Creatinine OR Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl): < 1.5x institution upper limit of normal OR greater than or equal to 45 mL/min/1.73 m^2 for participant with creatinine levels greater than or equal to 1.5 X institutional ULN. Note: Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard. The effects of the study treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment and up to 6 months after the last dose of the study drug (s). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Subjects must be able to understand and willing to sign a written informed consent document. EXCLUSION CRITERIA: Participants who are receiving any other investigational agents. Systemic anti-cancer treatment or major surgery within 2 weeks prior to enrollment. Radiotherapy within 24 hours prior to enrollment. Participants who require treatment with strong inhibitors or inducers of CYP3A or with UGT1A1 inhibitors during the planned period of investigational treatment with PLX038. Participants with known Gilbert s syndrome. Participants homozygous for the UGT1A1*28 variant allele with severely reduced UGT1A1 activity. Participants with known HIV, HCV, HBV status on antiviral drugs are excluded due to the absence of previous experience with concurrent use of antiviral medications and the investigational drug product to be evaluated in the current study and possible for adverse pharmacokinetic and/or pharmacodynamic interactions. History of allergic reactions attributed to compounds of similar chemical or biologic composition to PLX038 or rucaparib. 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 may impair the participants tolerance of study treatments. Pregnant women are excluded from this study because PEGSN38 and rucaparib potential for teratogenic or abortifacient effects are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with PEGSN38 and rucaparib, breastfeeding should be discontinued if the mother is treated with study drugs.

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: 1/Arm 1<br>Escalating doses of PLX038 and rucaparib | Drug: PLX038<br>* Phase I: Dose escalation will follow the classical 3+3 trial design by Fibonacci sequence. Phase II: MTD identified in phase I. PLX038 will be administered as a 1 hour (-10 minutes / +30 minutes) IV infusion on Day 1 of each cycle (21 days).<br>Drug: Rucaparib<br>* Phase I: Dose escalation will follow the classical 3+3 trial design by Fibonacci sequence. Phase II: MTD identified in phase I. Rucaparib will be given orally at designated dose twice a day on days 5 to 19 of every 21-day cycle.<br>|
| Experimental: 2/Arm 2<br>MTD of PLX038 and rucaparib | Drug: PLX038<br>* Phase I: Dose escalation will follow the classical 3+3 trial design by Fibonacci sequence. Phase II: MTD identified in phase I. PLX038 will be administered as a 1 hour (-10 minutes / +30 minutes) IV infusion on Day 1 of each cycle (21 days).<br>Drug: Rucaparib<br>* Phase I: Dose escalation will follow the classical 3+3 trial design by Fibonacci sequence. Phase II: MTD identified in phase I. Rucaparib will be given orally at designated dose twice a day on days 5 to 19 of every 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Clinical benefit rate | Assess the efficacy with respect to clinical benefit rate (CBR) (CR+PR+SD) for 4 months according to Response Evaluation Criteria (RECIST 1.1) of a combination of PLX038 and rucaparib in previously treated participants with small cell lung cancer and extra-pulmonary small cell carcinomas. | Disease progression | 
| Phase I: MTD | Identify the maximum tolerated dose (MTD) of PLX038 in combination with rucaparib. | Phase I | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities | The safety of the treatment will be monitored, and any toxicities identified will be reported by type and grade. | Phase I and phase II | 
| Progression-free survival | Among participants in the phase IIA cohort, median progression free survival (PFS) will be calculated from the on-study date using the Kaplan-Meier method, along with 95% confidence intervals on the median PFS. | Disease progression | 
| Overall survival | Among participants in the phase IIA cohort, median overall survival (OS) will be calculated from the on-study date using the Kaplan-Meier method, along with 95% confidence intervals on the median OS. | Death | 
| Clinical response rate | The fraction of participants who experience a clinical response (CR+PR) will be reported along with a 95% confidence interval. | Disease progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PARP Inhibitor, Chemotherapy, DDR Inhibitor