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

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ClinicalTrials.gov Identifier: NCT03919292
Recruitment Status : Recruiting
First Posted : April 18, 2019
Last Update Posted : May 3, 2019
Sponsor:
Collaborator:
Puma Biotechnology, Inc.
Information provided by (Responsible Party):
Virginia Commonwealth University

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 Intervention/treatment Phase
Solid Tumor, Adult Drug: Neratinib Drug: Divalproex Sodium 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.

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Study Type : Interventional  (Clinical Trial)
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 1, 2019
Estimated Primary Completion Date : January 31, 2022
Estimated Study Completion Date : January 31, 2024


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.
Other Name: Nerlynx

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).
Other Names:
  • Depakote
  • Valproate




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.



Information from the National Library of Medicine

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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:

  • 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/DrugInteractionsLabeling/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

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): NCT03919292


Contacts
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Contact: Andrew Poklepovic, MD 804-628-2321 andrew.poklepovic@vcuhealth.org
Contact: Massey SIIT Team 804-628-9238 masseysiit@vcu.edu

Locations
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United States, Virginia
Virginia Commonwealth University Massey Cancer Center Recruiting
Richmond, Virginia, United States, 23298
Contact: Kristen Bodine, RN    804-628-5273    klbodine@vcu.edu   
Contact: Massey SIIT    804-628-9238      
Principal Investigator: Andrew Poklepovic, MD         
Sponsors and Collaborators
Virginia Commonwealth University
Puma Biotechnology, Inc.
Investigators
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Principal Investigator: Andrew Poklepovic, MD Massey Cancer Center

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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: May 3, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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.: No

Keywords provided by Virginia Commonwealth University:
Colon Cancer
Pancreatic Cancer
Other solid tumor
Advanced solid tumor
Tumor progression

Additional relevant MeSH terms:
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Neoplasms
Valproic Acid
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs