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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04209595
Recruitment Status : Recruiting
First Posted : December 24, 2019
Last Update Posted : April 24, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE December 21, 2019
First Posted Date  ICMJE December 24, 2019
Last Update Posted Date April 24, 2020
Actual Study Start Date  ICMJE April 8, 2020
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 21, 2019)
  • Phase I: MTD [ Time Frame: Phase I ]
    Identify the maximum tolerated dose (MTD) of PLX038 in combination with rucaparib.
  • Phase II: Clinical benefit rate [ Time Frame: Disease progression ]
    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 patients with small cell lung cancer and extra-pulmonary small cell carcinomas.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2019)
  • Clinical response rate [ Time Frame: Disease progression ]
    The fraction of patients who experience a clinical response (CR+PR) will be reported along with a 95% confidence interval.
  • Overall survival [ Time Frame: Death ]
    Among patients 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.
  • Progression-free survival [ Time Frame: Disease progression ]
    Among patients 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.
  • Toxicities [ Time Frame: Phase I and phase II ]
    The safety of the treatment will be monitored, and any toxicities identified will be reported by type and grade.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE PLX038 (PEGylated SN38) and Rucaparib in Solid Tumors and Small Cell Cancers
Official Title  ICMJE Phase I/II Trial of PLX038 (PEGylated SN38) and Rucaparib in Solid Tumors and Small Cell Cancers.
Brief Summary

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

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 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy and for the treatment of adult patients with deleterious BRCA mutation- associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies.
  • 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 patients 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 3 to 19 of every cycle.
  • Treatment will continue until progression or unacceptable toxicity.
  • Biomarkers of patient response to treatment will be investigated in an exploratory manner pre and post-treatment.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Small Cell Lung Cancer
  • Extra-Pulmonary Small Cell Carcinomas
Intervention  ICMJE
  • Drug: PLX038
    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).
  • Drug: Rucaparib
    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 3 to 19 of every 21-day cycle. There should be a minimum 48-hour window between PLX038 and rucaparib.
Study Arms  ICMJE
  • Experimental: 1/Arm 1
    Escalating doses of PLX038 and rucaparib
    Interventions:
    • Drug: PLX038
    • Drug: Rucaparib
  • Experimental: 2/Arm 2
    MTD of PLX038 and rucaparib
    Interventions:
    • Drug: PLX038
    • Drug: Rucaparib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 21, 2019)
62
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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 patients <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.
  • Patients must have disease that is not amenable to potentially curative resection.
  • Patients must have measurable disease per RECIST 1.1. See Section 6.3 for the evaluation of measurable disease.
  • Patients 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 (or Legally Authorized Representative (LAR) for subjects who become decisionally impaired) must be able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA:

  • Patients 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.
  • Patients who require treatment with strong inhibitors or inducers of CYP3A or with UGT1A1 inhibitors during the planned period of investigational treatment with PLX038.
  • Patients with known Gilbert s syndrome.
  • Patients homozygous for the UGT1A1*28 variant allele with severely reduced UGT1A1 activity.
  • Patients 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 patient s 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Linda C Sciuto, R.N. (240) 760-6117 lsciuto@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04209595
Other Study ID Numbers  ICMJE 200013
20-C-0013
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Anish Thomas, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date April 22, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP