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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03919292
Recruitment Status : Recruiting
First Posted : April 18, 2019
Last Update Posted : September 23, 2022
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. Then to explore the antitumor effects of the neratinib and sodium valproate combination in advanced solid tumors with attention to RAS-mutated tumors, EGFR-altered GBM, and ocular melanoma, as part of the phase 2 expansion cohort.

Condition or disease Intervention/treatment Phase
Solid Tumor, Adult Drug: Neratinib Drug: Divalproex Sodium Phase 1 Phase 2

Detailed Description:

The purpose of this trial is to test the safety of combining 2 drugs, neratinib (Nerlynx) and divalproex sodium (Depakote DR), also commonly called valproate, when treating patients with advanced cancer.

In an earlier stage of this trial the purpose was to test different doses of neratinib in combination with divalproex sodium to see which doses should be used in future research trials. This trial will also help us to learn how advanced tumors respond to the combination of neratinib and divalproex sodium.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 113 participants
Allocation: Non-Randomized
Intervention Model: Sequential 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 : December 31, 2023
Estimated Study Completion Date : December 31, 2024


Arm Intervention/treatment
Experimental: Neratinib + Divalproex Sodium - Dose Escalation Cohort
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

Experimental: Colon
Colon Cancer (RAS-mutated) - Phase II dose expansion at recommended phase II dose (RP2D)
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

Experimental: Glioblastoma (GBM)
Glioblastoma with a RAS-mutation or EGFR alteration at RP2D
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

Experimental: Ocular Melanoma (OM)
Phase II dose expansion at RP2D
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

Experimental: Other Cancer
"Other Cancer" (RAS-mutated) at RP2D
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

Experimental: Pancreatic Cancer
RAS-mutated pancreatic cancer at RP2D
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 ]
    Determine the safety and toxicity of the combination of neratinib and sodium valproate by the number of participants with serious adverse events, and types of events as assessed by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.

  2. Solid Tumor Antitumor Effects [ Time Frame: 13 Months ]
    Phase 2 advanced solid tumor cohorts only: Evaluate number of participants with tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in patients evaluable for response.

  3. Glioblastoma Antitumor Effects [ Time Frame: 13 Months ]
    Phase 2 GBM cohort only: Evaluate number of participants with tumor control based on objective response based on Response Assessment in Neuro-Oncology (RANO) criteria or Macdonald criteria, or disease control defined as PFS ≥ 6-month in patients evaluable for response

  4. Progression Free Survival (PFS) [ Time Frame: 13 Months ]
    Evaluate the number of participants with progression free survival (PFS) defined as the duration of time from start of combination treatment (Cycle 1, Day 1) to date of 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 with a RAS mutation
  • Pancreatic Cancer with a RAS mutation
  • Other Solid Tumor with RAS Mutation
  • Ocular melanoma, which includes melanoma that develops in the sclera, retina, uvea (iris, choroid layer, and ciliary layer), or conjunctiva
  • Glioblastoma with a RAS mutation or EGFR alteration
  • Phase 1 and phase 2 advanced solid tumor cohorts excluding GBM: Measurable or evaluable disease by RECIST v1.1
  • Phase 2 GBM only: Pathologically confirmed high-grade glioma (WHO grade 3 or 4) with a RAS mutation or altered EGFR, with documented CT or MRI progression or recurrence. Biopsy is also an acceptable method of confirming progression. If initial tumor was grade 2 glioma, histological confirmation of high-grade recurrence is required
  • Phase 2 GBM only: Measurable or evaluable disease by RANO (MRI) or Macdonald (CT) criteria
  • Phase 2 GBM only: Fixed or decreasing dose of corticosteroids (or no corticosteroids) for at least 1 week prior to cycle 1 day 1.
  • Phase 2 GBM only: At least 12 weeks since the completion of radiation therapy to a total of ≥ 50 Gy

All patients must meet all of the following inclusion criteria to be eligible to participate in the study:

  • 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
  • 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:

  • Phase 1 and phase 2 advanced solid tumor cohorts excluding GBM: Current or prior known meningeal metastases
  • Phase 1 and phase 2 advanced solid tumor cohorts excluding GBM: 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 an enzyme inducing antiepileptic medication (EIAED)
  • 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: massey SIIT Team 804-628-9238 masseysiit@vcu.edu
Contact: Massey Team Delta ctoclinops@vcu.edu

Locations
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United States, Virginia
Virginia Commonwealth University Massey Cancer Center Recruiting
Richmond, Virginia, United States, 23298
Contact: Massey SIIT Team    804-628-9238    masseysiit@vcu.edu   
Contact: Massey Team Delta       ctoclinops@vcu.edu   
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
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT03919292    
Other Study ID Numbers: MCC-17-13821
First Posted: April 18, 2019    Key Record Dates
Last Update Posted: September 23, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to make individual participant data available to other researchers at this time.

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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