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出境医 / 临床实验 / Neratinib + Valproate in Advanced Solid Tumors, w/Expansion Cohort in Ras-Mutated Ca

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

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 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.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 participants
Allocation: N/A
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
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.
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

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
Layout table for eligibility information
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/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
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Massey SIIT Team 804-628-9238 Masseysiit@vcu.edu
Contact: Andrew Poklepovic, MD 877-462-7739

Locations
Layout table for location information
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: Andrew Poklepovic, MD    877-462-7739      
Principal Investigator: Andrew Poklepovic, MD         
Sponsors and Collaborators
Virginia Commonwealth University
Puma Biotechnology, Inc.
Investigators
Layout table for investigator information
Principal Investigator: Andrew Poklepovic, MD Massey Cancer Center
Tracking Information
First Submitted Date  ICMJE April 10, 2019
First Posted Date  ICMJE April 18, 2019
Last Update Posted Date March 11, 2021
Actual Study Start Date  ICMJE May 1, 2019
Estimated Primary Completion Date January 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 15, 2019)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 17, 2019)
  • 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.
  • Antitumor Effects [ Time Frame: 13 Months ]
    Tumor response, based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in patients evaluable for response.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 15, 2019)
  • Evaluation of Safety and Toxicity 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.
  • Antitumor Effects [ Time Frame: 13 Months ]
    Tumor response, based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in patients evaluable for response.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neratinib + Valproate in Advanced Solid Tumors, w/Expansion Cohort in Ras-Mutated Ca
Official Title  ICMJE Phase 1/2 Study of Neratinib and Divalproex Sodium (Valproate) in Advanced Solid Tumors, With an Expansion Cohort in Ras-Mutated Cancers
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumor, Adult
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Drug: Neratinib
  • Drug: Divalproex Sodium
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 15, 2019)
81
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 31, 2024
Estimated Primary Completion Date January 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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/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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Massey SIIT Team 804-628-9238 Masseysiit@vcu.edu
Contact: Andrew Poklepovic, MD 877-462-7739
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03919292
Other Study ID Numbers  ICMJE MCC-17-13821
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Virginia Commonwealth University
Study Sponsor  ICMJE Virginia Commonwealth University
Collaborators  ICMJE Puma Biotechnology, Inc.
Investigators  ICMJE
Principal Investigator: Andrew Poklepovic, MD Massey Cancer Center
PRS Account Virginia Commonwealth University
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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