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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) )

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....


Condition or disease Intervention/treatment Phase
Small Cell Lung Cancer Extra-Pulmonary Small Cell Carcinomas Drug: PLX038 Drug: Rucaparib Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial of PLX038 (PEGylated SN38) and Rucaparib in Solid Tumors and Small Cell Cancers.
Actual Study Start Date : April 8, 2020
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Rucaparib

Arm Intervention/treatment
Experimental: 1/Arm 1
Escalating doses of PLX038 and rucaparib
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.

Experimental: 2/Arm 2
MTD of PLX038 and rucaparib
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.




Primary Outcome Measures :
  1. Phase I: MTD [ Time Frame: Phase I ]
    Identify the maximum tolerated dose (MTD) of PLX038 in combination with rucaparib.

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04209595


Contacts
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Contact: Linda C Sciuto, R.N. (240) 760-6117 lsciuto@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Anish Thomas, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04209595    
Other Study ID Numbers: 200013
20-C-0013
First Posted: December 24, 2019    Key Record Dates
Last Update Posted: April 24, 2020
Last Verified: April 22, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
PARP Inhibitor
Chemotherapy
DDR Inhibitor
Additional relevant MeSH terms:
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Small Cell Lung Carcinoma
Carcinoma, Small Cell
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Rucaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents