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

NCT04209595 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 20001320-C-0013
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Drugs known as poly-adenosine diphosphate ribose polymerase (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 types 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 (PEGylated SN38) 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, small cell lung cancer (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....

Conditions

Small Cell Lung Cancer; Extra-Pulmonary Small Cell Carcinomas

Keywords

PARP Inhibitor; Chemotherapy; DDR Inhibitor

Outcome Measures

Primary Outcomes (2)

• Phase II: Clinical Benefit Rate

  Assess the efficacy with respect to clinical benefit rate (CBR) (Complete Response (CR)+ partial response (PR)+ stable disease (SD) for 4 months according to Response Evaluation Criteria (RECIST 1.1) of a combination of PLX038(PEGylated SN38) and rucaparib in previously treated participants with small cell lung cancer and extra-pulmonary small cell carcinomas. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study.

  Disease progression at 4 months

• Phase I: Maximum Tolerated Dose (MTD) of PLX038 (PEGylated SN38) in Combination With Rucaparib

  Maximum tolerated dose (MTD) of PLX038 (PEGylated SN38) in combination with rucaparib. The MTD is the dose level at which no more than 1 of 6 participants experience dose limiting toxicity (DLT) during the DLT evaluation period, and the dose below that at which at least 2 (of 6) participants have DLT as a result of the drug. A DLT is (if deemed drug-related) a Grade 4 neutropenia that does not resolve within 7 days; Grade 4 thrombocytopenia or grade 3 thrombocytopenia complicated with hemorrhage; Grade 4 anemia that does not resolve within 7 days despite optimal therapy; Inability to begin subsequent treatment course within 21 days of the scheduled date, due to study drug toxicity.

  One cycle, approximately 21 (+7) days

Secondary Outcomes (4)

• Phase I and Phase II Grades 1-5 Serious and/or Non-serious Adverse Events Related to PLX038 (PEGylated SN38) and/or Rucaparib

  Date first signed consent to date off study, approximately 21 months and 18 days; and 2 months and 5 days for each group respectively.

• Phase IIA Progression-free Survival (PFS)

  Time from the on-study date to documented evidence of disease progression

• Phase IIA Overall Survival

  Date of on-study to the date of death from any cause or last follow-up

• Phase I - Number of Participants Who Experience a Clinical Response (Complete Response (CR)+Partial Response (PR)

  Disease progression, a median of 43 days with range of 20 to 350 days.

Other Outcomes (2)

• Phase I Number of Participants With a Dose Limiting Toxicity (DLT)

  One cycle, approximately 21 days

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date first signed consent to date off study, approximately 21 months and 18 days; and 2 months and 5 days for each group respectively.

Study Arms (5)

Phase I Arm 1 Level -1A, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 200 mg

EXPERIMENTAL

Phase I - Participants with solid tumors enrolled to PLX038 (PEGylated SN38) and rucaparib escalation dose levels. PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 200 mg by mouth (PO)

Drug: PLX038; Drug: Rucaparib; Drug: Ondansetron

Phase I Arm 1 Level 1, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 400 mg

EXPERIMENTAL

Phase I - Participants with solid tumors enrolled to PLX038 (PEGylated SN38) and rucaparib escalation dose levels. PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 400 mg by mouth (PO)

Drug: PLX038; Drug: Rucaparib; Drug: Ondansetron

Phase I - Arm 1 Level 1A, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 300 mg

EXPERIMENTAL

Phase I Participants with solid tumors enrolled to PLX038 (PEGylated SN38) and rucaparib escalation dose levels. PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 300 mg by mouth (PO)

Drug: PLX038; Drug: Rucaparib; Drug: Ondansetron

Phase IIA Arm 2

EXPERIMENTAL

Phase IIA Participants with small cell lung cancer (SCLC) enrolled at the maximum tolerated dose (MTD) of PLX038 (PEGylated SN38) and rucaparib after the MTD of PLX038 and rucaparib is established. Level 2, PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 3, PLX038, every 3 weeks, 1.7 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 4, PLX038, every 3 weeks, 2.3 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 2A PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 400 mg by mouth (PO); and/or Level 3A. PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 600 mg by mouth (PO).

Drug: PLX038; Drug: Rucaparib; Drug: Ondansetron

Phase IIB Arm 2

EXPERIMENTAL

Phase IIB Participants with extra-pulmonary small cell carcinomas enrolled at the maximum tolerated dose (MTD) of PLX038 (PEGylated SN38) and rucaparib after the MTD of PLX038 and rucaparib is established. Level 2, PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 3, PLX038, every 3 weeks, 1.7 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 4, PLX038, every 3 weeks, 2.3 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 2A PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 400 mg by mouth (PO); and/or Level 3A. PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 600 mg by mouth (PO).

Drug: PLX038; Drug: Rucaparib; Drug: Ondansetron

Interventions

PLX038 DRUG

Phase I: Dose escalation will follow the classical 3+3 trial design by Fibonacci sequence. Phase II: Maximum tolerated dose (MTD) identified in phase I. PLX038 (PEGylated SN38) will be administered as a 1 hour (-10 minutes / +30 minutes) intravenous (IV) infusion on Day 1 of each cycle (21 days).

Also known as: PEGylated SN38

Phase I - Arm 1 Level 1A, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 300 mg; Phase I Arm 1 Level -1A, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 200 mg; Phase I Arm 1 Level 1, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 400 mg; Phase IIA Arm 2; Phase IIB Arm 2

Rucaparib DRUG

Phase I: Dose escalation will follow the classical 3+3 trial design by Fibonacci sequence. Phase II: Maximum tolerated dose (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.

Also known as: Rubraca

Phase I - Arm 1 Level 1A, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 300 mg; Phase I Arm 1 Level -1A, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 200 mg; Phase I Arm 1 Level 1, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 400 mg; Phase IIA Arm 2; Phase IIB Arm 2

Ondansetron DRUG

Participants will be recommended to have 8 mg of ondansetron taken with a small meal or snack to prevent nausea and vomiting approximately 30 minutes prior to each dose of rucaparib.

Also known as: Zofran

Phase I - Arm 1 Level 1A, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 300 mg; Phase I Arm 1 Level -1A, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 200 mg; Phase I Arm 1 Level 1, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 400 mg; Phase IIA Arm 2; Phase IIB Arm 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Small Cell Lung Carcinoma

Interventions

rucaparib; Ondansetron

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Results Point of Contact

• Title: Dr. Anish Thomas
• Organization: National Cancer Institute

anish.thomas@nih.gov

240-760-7343

Study Officials

• Anish Thomas, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 21, 2019
• First Posted: December 24, 2019
• Study Start: April 8, 2020
• Primary Completion: August 13, 2021
• Study Completion: February 24, 2025
• Last Updated: March 17, 2025
• Results First Posted: January 3, 2024

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)