Clinical Trials /

Niraparib and Neratinib in Advanced Solid Tumors With Expansion Cohort in Advanced Ovarian Cancer

NCT04502602

Description:

To determine the recommended phase 2 dose (RP2D) of niraparib and neratinib in combination in patients with advanced solid tumors during Phase 1. To evaluate clinical benefit (≥4-month progression-free survival [PFS]) of niraparib and neratinib in patients with platinum-resistant ovarian cancer in Phase 1b.

Related Conditions:
  • Malignant Solid Tumor
  • Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Niraparib and Neratinib in Advanced Solid Tumors With Expansion Cohort in Advanced Ovarian Cancer
  • Official Title: A Phase 1/1b Clinical Trial of Niraparib and Neratinib in Advanced Solid Tumors With an Expansion Cohort in Platinum-resistant Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: MCC-18-14152
  • SECONDARY ID: NCI-2020-05315
  • NCT ID: NCT04502602

Conditions

  • Advanced Solid Tumor
  • Ovarian Cancer

Interventions

DrugSynonymsArms
Neratinib 160 mgDose Level -1
Neratinib 200 mgDose Level 2
Neratinib 240 mgDose Level 3
Niraparib 100 mgDose Level -1
Niraparib 200 mgDose Level 1
Niraparib 300 mgDose Level 4
Niraparib at RP2DPhase 1b: Platinum Resistant Expansion Cohort
Neratinib at RP2DPhase 1b: Platinum Resistant Expansion Cohort

Purpose

To determine the recommended phase 2 dose (RP2D) of niraparib and neratinib in combination in patients with advanced solid tumors during Phase 1. To evaluate clinical benefit (≥4-month progression-free survival [PFS]) of niraparib and neratinib in patients with platinum-resistant ovarian cancer in Phase 1b.

Detailed Description

      This study is a single-arm, open-label, phase 1/1b trial to determine the RP2D of neratinib
      and niraparib when given in combination to patients with advanced solid tumors. The RP2D will
      be identified during the phase 1 dose escalation portion of the study using a modified 3+3
      design and evaluated in a phase 1b dose expansion cohort of up to 12 patients with
      platinum-resistant ovarian cancer.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Level -1ExperimentalNeratinib 160 mg and Niraparib 100 mg by mouth once daily for 28 day cycles.
  • Neratinib 160 mg
  • Niraparib 100 mg
Dose Level 1ExperimentalNeratinib 160 mg and Niraparib 200 mg by mouth once daily for 28 day cycles.
  • Neratinib 160 mg
  • Niraparib 200 mg
Dose Level 2ExperimentalNeratinib 200 mg and Niraparib 200 mg by mouth once daily for 28 day cycles.
  • Neratinib 200 mg
  • Niraparib 200 mg
Dose Level 3ExperimentalNeratinib 240 mg and Niraparib 200 mg by mouth once daily for 28 day cycles.
  • Neratinib 240 mg
  • Niraparib 200 mg
Dose Level 4ExperimentalNeratinib 240 mg and Niraparib 300 mg by mouth once daily for 28 day cycles.
  • Neratinib 240 mg
  • Niraparib 300 mg
Phase 1b: Platinum Resistant Expansion CohortExperimentalThis portion of the study provides for cohort expansion to observe for 4 month or greater progression-free survival in patients with platinum resistant ovarian cancer treated at the recommended phase 2 dose (RP2D) determined in Phase I.
  • Niraparib at RP2D
  • Neratinib at RP2D

Eligibility Criteria

        Inclusion Criteria:

          -  Disease Characteristics

          -  Phase 1: Patients with advanced solid tumors, excluding primary CNS and prostate
             tumors, that have progressed during or after treatment with approved therapies or for
             which there is no standard effective therapy available or

          -  Phase 1b: Female patients with ovarian cancer who:

               -  Are platinum resistant (progressed within 6 months of finishing platinum therapy)
                  and

               -  Have received at least 2 prior lines of therapy and

               -  Do not have a BRCA germline mutation

          -  Measurable or evaluable disease by RECIST 1.1

          -  Age ≥ 18 years

          -  ECOG performance status 0 or 1

          -  Adequate bone marrow function as defined below:

               -  Absolute neutrophil count (ANC) ≥ 1,500/mm3

               -  Platelets ≥ 100,000/mm3 (untransfused)

               -  Hemoglobin ≥9 g/dL (untransfused)

          -  Adequate renal function as defined below:

               -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for the laboratory OR
                  calculated

               -  Or actual creatinine clearance ≥ 30 mL/min (see Appendix 2 for the
                  Cockcroft-Gault formula for calculating creatinine clearance)

          -  Adequate hepatic function as defined below:

               -  Total bilirubin ≤ 1.5 x ULN for the laboratory OR direct bilirubin ≤ 1.0 x ULN

               -  Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN (≤ 3x ULN
                  when liver metastases are present)

          -  Patients receiving corticosteroids may continue as long as their dose is stable for
             least 4 weeks prior to initiating protocol therapy

          -  Patients must agree not to donate blood during the study or for 90 days after the last
             dose of study treatment

          -  A woman of childbearing potential (WCBP) must have a documented negative serum
             pregnancy test within 7 days prior to initiating study treatment and agree to abstain
             from activities that could result in pregnancy from screening through 180 days after
             the last dose of study treatment. Non Childbearing potential is defined as follows (by
             other than medical reasons):

               -  ≥45 years of age and has not had menses for >1 year

               -  Patients who have been amenorrhoeic for <2 years without history of a
                  hysterectomy and oophorectomy must have a follicle stimulating hormone (FSH)
                  value in the postmenopausal range upon screening evaluation

               -  Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.
                  Documented hysterectomy or oophorectomy must be confirmed with medical records of
                  the actual procedure or confirmed by an ultrasound. Tubal ligation must be
                  confirmed with medical records of the actual procedure, otherwise the patient
                  must be willing to use 2 adequate barrier methods throughout the study, starting
                  with the screening visit through 180 days after the last dose of study treatment.
                  Information must be captured appropriately within the site's source documents.
                  Note: Abstinence is acceptable if this is the established and preferred
                  contraception for the patient.

          -  Participant must agree to not breastfeed during the study or for 180 days after the
             last dose of study treatment.

          -  Male participant agrees to use an adequate method of contraception starting with the
             first dose of study treatment through 90 days after the last dose of study treatment.
             Note: Abstinence is acceptable if this is the established and preferred contraception
             for the patient.

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Any investigational agent within 4 weeks, or within a time interval less than at least
             5 half-lives of the investigational agent, whichever is shorter, prior to initiating
             study treatment

          -  Simultaneous enrollment in any other interventional clinical trial

          -  Active, uncontrolled diarrhea leading to dehydration or electrolyte disturbances not
             controlled with oral repletion

          -  Serious (ie, grade ≥ 3) uncontrolled infection

          -  Major surgery ≤ 3 weeks prior to initiating study treatment and patient must have
             recovered from any surgical effects.

          -  Radiation encompassing >20% of the bone marrow within 2 weeks, or any radiation
             therapy within 1 week, prior to initiating study treatment.

          -  Transfusion of platelets or red blood cells ≤ 4 weeks prior to initiating study
             treatment

          -  Receipt of colony-stimulating factors (e.g., granulocyte colony-stimulating factor
             [GCSF], granulocyte macrophage colony- stimulating factor [GM-CSF], or recombinant
             erythropoietin) within 4 weeks prior to initiating study treatment

          -  Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)

          -  Known brain or leptomeningeal metastasis

          -  Diagnosis, detection, or treatment of another type of invasive cancer ≤ 2 years prior
             to initiating study treatment

          -  Active or clinically significant cardiac disease including any of the following;

               -  Unstable angina (eg, angina symptoms at rest) or onset of angina within 3 months
                  prior to initiating study treatment

               -  Myocardial infarction diagnoses within 6 months prior to initiating study
                  treatment

               -  New York Heart Association (NYHA) class III or IV congestive heart failure

          -  Inability to swallow medication

          -  Known hypersensitivity to niraparib or neratinib components or excipients

          -  Known or suspected malabsorption condition or obstruction Note: Use of pancreatic
             enzyme supplements is allowed to control malabsorption

          -  Inability to shift medications as follows:

               -  Antacids (eg, calcium carbonate): dose at least 3 hours after dosing with
                  neratinib

               -  H2 receptor antagonists: dose must be taken at least 2 hours after or 10 hours
                  before dosing with neratinib

          -  Planned ongoing treatment with other drugs thought to potentially have adverse
             interactions with either of the medications included in the study treatment:

               -  Proton pump inhibitors (PPIs).

               -  High-risk P-glycoprotein (P-gp) substrates (eg, digoxin, dabigatran).

               -  Strong or moderate CYP3A4 inhibitors and/or Strong or moderate CYP3A4 inducers.
                  Examples of clinical inhibitors and clinical inducers for P450-mediated
                  metabolism and classification of strong, moderate, and weak interactions are
                  available through the FDA website:
                  http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInte
                  ractionsLabeling/ucm093664.htm

               -  If such medications have been used, patients must have discontinued these agents
                  ≥ 2 weeks prior to initiating study treatment.

          -  Pregnancy or breastfeeding

          -  Medical, psychological, or social condition that, in the opinion of the investigator,
             may increase the patient's risk or limit the patient's adherence with study
             requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: To determine the Recommended phase 2 dose (RP2D) of niraparib and neratinib in patients with advanced solid tumors
Time Frame:4 Months
Safety Issue:
Description:The RP2D will be identified during the phase 1 dose escalation portion of the study using a modified 3+3 design and evaluated in a phase 1b dose expansion cohort of up to 12 patients with platinum-resistant ovarian cancer.

Secondary Outcome Measures

Measure:To assess the frequency of adverse events (AEs)
Time Frame:5 months
Safety Issue:
Description:To assess adverse events (AEs) characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE V 5.0) to determine safety and toxicity of the combination of neratinib and niraparib
Measure:Preliminary efficacy (objective response rate [ORR]) of niraparib and neratinib in patients with advanced solid tumors.
Time Frame:5 years
Safety Issue:
Description:To evaluate the objective response rate (ORR): The percentage of patients with objective response either partial response (PR) or complete response(CR), by analysis using RECIST 1.1 criteria

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Virginia Commonwealth University

Last Updated

August 4, 2020