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

Background:

• We hypothesize that a dose-escalation strategy that incorporates tumor targeted deoxyribonucleic acid (DNA)-damaging chemotherapy and DNA-damage response (DDR) inhibitors could allow safe and effective administration of DNA damage response (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.
• Eastern Cooperative Oncology Group (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 intravenous (IV) infusion on day 1 of every 21-days cycle, rucaparib will be administered by mouth (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.

• INCLUSION CRITERIA:
• 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. Because no dosing or adverse event data are currently available on the use of PLX038 (PEGylated SN38) 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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Participants with asymptomatic brain metastases and treated brain metastases are eligible.
• Eastern Cooperative Oncology Group (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,
• Hemoglobin (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 upper limit of normal (ULN),
• an aspartate aminotransferase (AST) level less than or equal to 2.5xULN, (less than or equal to 5X ULN if liver metastasis)
• an alanine transaminase (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) (estimated glomerular filtration rate (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 Cytochrome P450, family 3, subfamily A (CYP3A) or with uridine diphosphate glucuronosyltransferase 1A1 gene (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 human immunodeficiency virus (HIV), hepatitis C virus (HCV), Hepatitis B virus (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.