Clinical Trials /

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

NCT04209595

Description:

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....

Related Conditions:
  • Malignant Solid Tumor
  • Small Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 200013
  • SECONDARY ID: 20-C-0013
  • NCT ID: NCT04209595

Conditions

  • Small Cell Lung Cancer
  • Extra-Pulmonary Small Cell Carcinomas

Interventions

DrugSynonymsArms
PLX0381/Arm 1
Rucaparib1/Arm 1

Purpose

Background: Solid tumors (such as sarcomas, carcinomas, and lymphomas) and small cell cancers (such as small cell lung cancer, or SCLC) are treated with radiation, chemotherapy, and surgery. A drug called PLX038, when given with an anti-cancer drug, also may be able to help. 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 <TAB>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 or magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis. CT scans are a series of X-rays. MRIs use magnetic fields and radio waves to take pictures. 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
1/Arm 1ExperimentalEscalating doses of PLX038 and rucaparib
  • PLX038
  • Rucaparib
2/Arm 2ExperimentalMTD of PLX038 and rucaparib
  • PLX038
  • Rucaparib

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: MTD
Time Frame:Phase I
Safety Issue:
Description:Identify the maximum tolerated dose (MTD) of PLX038 in combination with rucaparib.

Secondary Outcome Measures

Measure:Clinical response rate
Time Frame:Disease progression
Safety Issue:
Description:The fraction of patients who experience a clinical response (CR+PR) will be reported along with a 95% confidence interval.
Measure:Overall survival
Time Frame:Death
Safety Issue:
Description: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.
Measure:Progression-free survival
Time Frame:Disease progression
Safety Issue:
Description: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.
Measure:Toxicities
Time Frame:Phase I and phase II
Safety Issue:
Description:The safety of the treatment will be monitored, and any toxicities identified will be reported by type and grade.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • PARP Inhibitor
  • Chemotherapy
  • DDR Inhibitor

Last Updated

December 26, 2019