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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 01/24/2021.

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

Clinicaltrials.gov identifier NCT03919292

Recruitment Status Recruiting

First Posted April 18, 2019

Last update posted February 20, 2020

Study Description

Brief summary:

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

  • Condition or Disease:Solid Tumor, Adult
  • Intervention/Treatment: Drug: Neratinib
    Drug: Divalproex Sodium
  • Phase: Phase 1/Phase 2
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.

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 81 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: Phase 1/2 Study of Neratinib and Divalproex Sodium (Valproate) in Advanced Solid Tumors, With an Expansion Cohort in Ras-Mutated Cancers
  • Actual Study Start Date: May 2019
  • Estimated Primary Completion Date: January 2022
  • Estimated Study Completion Date: January 2024
Arms and interventions
Arm Intervention/treatment
Experimental: Neratinib + Divalproex Sodium
Neratinib by mouth (PO) once daily + Divalproex Sodium (Valproate) by mouth (PO) twice daily on days 1-28 of each course.
Drug: Neratinib
Combination of Neratinib and Divalproex Sodium (Valproate) will be given to patients with advanced solid tumors (dose escalation) and Ras-mutated cancers (dose expansion). Doses of Neratinib are escalated in small groups of patients during the dose expansion portion of the study.

Drug: Divalproex Sodium
Combination of Neratinib and Divalproex Sodium (Valproate) will be given to patients with advanced solid tumors (dose escalation) and Ras-mutated cancers (dose expansion).
Outcome Measures
  • Primary Outcome Measures: 1. Determination of Recommended Phase 2 Dose (RP2D) [ Time Frame: 28 Days ]
    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: 1. Evaluation of Treatment Related Adverse Events of Neratinib combined with Sodium Valproate [ Time Frame: 13 Months ]
    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.
  • 2. Antitumor Effects [ Time Frame: 13 Months ]
    Tumor response, based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in patients evaluable for response.
  • 3. Progression Free Survival (PFS) [ Time Frame: 13 Months ]
    To evaluate PFS as the duration from the start of Cycle 1 Day 1 to the date of tumor progression.
Eligibility Criteria
  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No
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

- Total 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.

- Aspartate 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

Contacts and Locations
Contacts

Contact: Massey SIIT Team 804-628-9238 Masseysiit@vcu.edu

Contact: Andrew Poklepovic, MD 877-462-7739

Locations

United States, Virginia
Virginia Commonwealth University Massey Cancer Center
Richmond

Sponsors and Collaborators

Virginia Commonwealth University

Puma Biotechnology, Inc.

Investigators

Principal Investigator: Andrew Poklepovic, MD Massey Cancer Center

More Information
  • Responsible Party: Virginia Commonwealth University
  • ClinicalTrials.gov Identifier: NCT03919292 History of Changes
  • Other Study ID Numbers: MCC-17-13821
  • First Posted: April 18, 2019 Key Record Dates
  • Last Update Posted: February 20, 2020
  • Last Verified: February 2020
  • Individual Participant
    Data (IPD) Sharing
    Statement:
  • Plan to Share IPD: No
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Product Manufactured in and Exported from the U.S.: Yes
  • Keywords provided by Virginia Commonwealth University: Colon Cancer
    Pancreatic Cancer
    Other solid tumor
    Advanced solid tumor
    Tumor progression
  • Additional relevant MeSH terms: Neoplasms