Clinical Trials /

Neratinib + Valproate in Advanced Solid Tumors, w/Expansion Cohort in Ras-Mutated Ca

NCT03919292

Description:

To determine the recommended phase 2 dose (RP2D) of the combination of neratinib and sodium valproate when given to patients with advanced solid tumors.

Related Conditions:
  • Colon Carcinoma
  • Malignant Solid Tumor
  • Pancreatic Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neratinib + Valproate in Advanced Solid Tumors, w/Expansion Cohort in Ras-Mutated Ca
  • Official Title: Phase 1/2 Study of Neratinib and Divalproex Sodium (Valproate) in Advanced Solid Tumors, With an Expansion Cohort in Ras-Mutated Cancers

Clinical Trial IDs

  • ORG STUDY ID: MCC-17-13821
  • NCT ID: NCT03919292

Conditions

  • Solid Tumor, Adult

Interventions

DrugSynonymsArms
NeratinibNerlynxNeratinib + Divalproex Sodium
Divalproex SodiumDepakote, ValproateNeratinib + Divalproex Sodium

Purpose

To determine the recommended phase 2 dose (RP2D) of the combination of neratinib and sodium valproate when given to patients with advanced solid tumors.

Detailed Description

      This study is a single-arm, open-label, phase 1/2 trial to determine the recommended phase 2
      dose of neratinib and sodium valproate when given in combination to patients with advanced
      solid tumors in 28 day cycles. The phase II portion of the study will evaluate the
      combination at the RP2D in 3 cohorts of RAS mutated tumors, KRAS mutant colorectal cancer,
      KRAS mutant pancreatic cancer, and K or N RAS mutant solid tumors.
    

Trial Arms

NameTypeDescriptionInterventions
Neratinib + Divalproex SodiumExperimentalNeratinib by mouth (PO) once daily + Divalproex Sodium (Valproate) by mouth (PO) twice daily on days 1-28 of each course.
  • Neratinib
  • Divalproex Sodium

Eligibility Criteria

        Inclusion Criteria:

          -  Phase 1 - Dose Escalation Phase: Advanced solid tumor that has progressed during or
             after treatment with approved therapies or for which there is no standard effective
             therapy available

          -  Phase 2 - Dose Expansion Phase: One of the following advanced solid tumors that is
             RAS-mutated and has progressed during or after treatment with approved therapies or
             for which there is no standard effective therapy available: :

          -  Colon Cancer

          -  Pancreatic Cancer

          -  Other Solid Tumor

          -  Measurable or evaluable disease by RECIST v1.1

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Adequate bone marrow function

          -  Absolute neutrophil count (ANC) ≥ 1500/mm3

          -  Platelets ≥ 100,000/mm3

          -  Hemoglobin > 9 g/dL (untransfused)

          -  Adequate renal function

          -  Creatinine ≤ 1.5 x upper limit of normal (ULN) for the laboratory or calculated or
             actual creatinine clearance ≥ 60 mL/min

          -  Adequate hepatic function

          -  otal bilirubin ≤ 1.5 x ULN for the laboratory Exception: If a patient has documented
             Gilbert's syndrome and a total bilirubin is > 1.5 x ULN for the laboratory, the total
             bilirubin requirement may be waived provided the direct bilirubin is within normal
             limits (WNL) for the laboratory.

          -  spartate aminotransferase (AST) ≤ 3.0 x ULN for the laboratory

          -  Alanine aminotransferase (ALT) ≤ 3.0 x ULN for the laboratory

          -  Note: For the expansion cohorts, in patients with documented liver metastasis, the AST
             and ALT requirements will be ≤ 5 x ULN for the laboratory

          -  Non-hematologic toxicities from previous cancer therapies resolved to ≤ grade 1 except
             chronic residual toxicities that in the opinion of the investigator are not clinically
             relevant given the known safety/toxicity profiles of neratinib and sodium valproate
             (eg, alopecia, changes in pigmentation, stable endocrinopathies, neuropathy, skin
             toxicities)

          -  International normalized ratio (INR) is ≤ 1.5 and activated partial thromboplastin
             time (aPTT) ≤ 1.5 x ULN for the laboratory

          -  Left ventricular ejection fraction (LVEF) within 3 months prior to initiation of study
             treatment indicates an LVEF of ≥ 50%.

          -  A woman of childbearing potential (WCBP), defined as a woman who is < 60 years of age
             and has not had a hysterectomy, must have a documented negative serum pregnancy test
             within 7 days prior to initiating study treatment

          -  WCBP and a male patient with a partner who is a WCBP must agree to use a medically
             accepted method for preventing pregnancy for the duration of study treatment and for 2
             months following completion of study treatment

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

        Exclusion Criteria:

          -  Current or prior known meningeal metastases

          -  Known brain metastases that are symptomatic or untreated. Note: Patients with known
             brain metastases who are asymptomatic and have had post-treatment imaging that
             indicates stable brain disease are eligible. Note that brain imaging in patients with
             known brain metastases is required within 8 weeks prior to initiation of study
             therapy.

          -  Any investigational agent within 4 weeks prior to initiating study treatment

          -  Previous therapy with neratinib

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

          -  Inability to swallow medication

          -  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

          -  Resting systolic blood pressure (BP) < 100 mmHg

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

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

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

          -  Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers

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

          -  Seizure disorder requiring medication other than sodium valproate

          -  Serious (ie, ≥ grade 3) uncontrolled infection

          -  Chronic or active hepatitis B or C infection with elevated transaminase levels

          -  Pleural effusion or ascites that causes respiratory compromise (ie, ≥ grade 2 dyspnea)

          -  Known mitochondrial disorder caused by mutations in mitochondrial DNA polymerase gamma
             (γ)

          -  Known urea cycle disorders

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

          -  Cosyntropin

          -  Proton pump inhibitors (PPIs)

          -  High-risk P-glycoprotein (P-gp) substrates (eg, digoxin, dabigatran, fexofenadine).
             Other anticoagulants are not considered high-risk P-gp substrates

          -  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, Tables 3-2 and 3-3:
             http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
             onsLabeling/ucm093664.htm Note: 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:Determination of Recommended Phase 2 Dose (RP2D)
Time Frame:28 Days
Safety Issue:
Description:RP2D for the combination of neratinib and sodium valproate that is less than or the same as the maximum tolerated dose (MTD).

Secondary Outcome Measures

Measure:Evaluation of Treatment Related Adverse Events of Neratinib combined with Sodium Valproate
Time Frame:13 Months
Safety Issue:
Description:To determine the safety and toxicity of the combination of neratinib and sodium valproate by characterizing, grading, and evaluating the serious adverse events, and adverse events the patients experience utilizing the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.
Measure:Antitumor Effects
Time Frame:13 Months
Safety Issue:
Description:Tumor response, based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in patients evaluable for response.
Measure:Progression Free Survival (PFS)
Time Frame:13 Months
Safety Issue:
Description:To evaluate PFS as the duration from the start of Cycle 1 Day 1 to the date of tumor progression.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Virginia Commonwealth University

Trial Keywords

  • Colon Cancer
  • Pancreatic Cancer
  • Other solid tumor
  • Advanced solid tumor
  • Tumor progression

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