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Combination Trial of Tipifarnib and Alpelisib in Adult Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC)

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ClinicalTrials.gov Identifier: NCT04997902
Recruitment Status : Recruiting
First Posted : August 10, 2021
Last Update Posted : August 30, 2022
Sponsor:
Information provided by (Responsible Party):
Kura Oncology, Inc.

Study Description
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Brief Summary:
This phase 1/2 combination trial of tipifarnib, a farnesyltransferase inhibitor, and alpelisib, a PI3K inhibitor in participants with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) whose tumors overexpress the HRAS protein and/or are PIK3CA-mutated and/or PIK3CA-amplified.

Condition or disease Intervention/treatment Phase
HNSCC Drug: Tipifarnib Drug: Alpelisib Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Open-label, Biomarker-defined Cohort Trial to Evaluate the Safety, Determine the Recommended Combination Dosing, and Assess Early Antitumor Activity of Tipifarnib and Alpelisib for the Treatment of Adult Participants Who Have HRAS-overexpressing and/or PIK3CA-mutated and/or - Amplified Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
Actual Study Start Date : December 7, 2021
Estimated Primary Completion Date : September 2024
Estimated Study Completion Date : September 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: PIK3CA-dependent (Cohort 1)
Adult participants with R/M HNSCC whose tumors harbor PI3KCA (activating) mutations and/or amplifications
 Drug: Tipifarnib
Oral administration

Drug: Alpelisib
Oral administration
Other Name: BYL719
Experimental: HRAS-dependent (Cohort 2)
Adult participants with R/M HNSCC whose tumors have increased HRAS dependency, defined as HRAS overexpression
 Drug: Tipifarnib
Oral administration

Drug: Alpelisib
Oral administration
Other Name: BYL719


Outcome Measures
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Primary Outcome Measures :
  1. To determine the recommended dose and regimen and evaluate the safety and tolerability of the combination of tipifarnib and alpelisib [ Time Frame: DLTs will be evaluated during the first 28 days (1 cycle) of combination therapy ]
    Rate of DLT per dose level and Descriptive statistics of adverse events per the NCI CTCAE v 5.0


Secondary Outcome Measures :
  1. Determine the Objective Response Rate (ORR) [ Time Frame: Up to approximately 3 years ]
    Overall confirmed response rate (CR + PR) and Median duration of response

  2. Disease control rate (DCR) [ Time Frame: Up to approximately 3 years ]
    Disease control rate (CR + PR + SD), Median duration of disease control, Rate of SD, Median duration of SD

  3. Cmax of tipifarnib and alpelisib when administered in combination [ Time Frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days. ]
    Peak drug concentration for single dose and multiple dose

  4. Tmax of tipifarnib and alpelisib when administered in combination [ Time Frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days. ]
    Time to reach peak concentration following drug administration for single dose and multiple dose

  5. AUC(0-last) of tipifarnib and alpelisib when administered in combination [ Time Frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days. ]
    Area under the concentration-time curve from time zero to time of last measurable concentration for single dose and multiple dose

  6. AUC(tau) of tipifarnib and alpelisib when administered in combination [ Time Frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days. ]
    Area under the concentration-time curve during a dosage interval for single dose and multiple dose

  7. AUC(0-infinity) of tipifarnib and alpelisib when administered in combination [ Time Frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days. ]
    Area under the concentration-time curve from time zero to infinity for single dose

  8. CL/F of tipifarnib and alpelisib when administered in combination [ Time Frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days. ]
    Apparent total clearance of the drug after administration for single dose and multiple dose

  9. Vd/F of tipifarnib and alpelisib when administered in combination [ Time Frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days. ]
    Apparent volume of distribution after administration for single dose and multiple dose

  10. Half-life of tipifarnib and alpelisib when administered in combination [ Time Frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days. ]
    Time required for the amount of drug in the body to decrease by half for single dose and multiple dose

  11. Accumulation ratio of tipifarnib and alpelisib when administered in combination [ Time Frame: Blood samples will be collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6. Each cycle is 28 days. ]
    Ratio of accumulation of a drug after multiple doses compared to a single dose

  12. Antitumor activity in terms of PFS and rate of PFS at 6 months [ Time Frame: Up to approximately 3 years ]
    Median PFS and Proportion of participants alive and without progression at 6 months

  13. Overall Survival (OS) and rate of OS at 12 months [ Time Frame: Up to approximately 3 years ]
    Median OS and Proportion of participants alive at 12 months


Eligibility Criteria
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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:

  1. At least 18 years of age.
  2. Histologically confirmed head and neck cancer of squamous histology not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).
  3. Documented treatment failure from at least 1 prior systemic therapy in the R/M setting, unless determined not appropriate.
  4. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
  5. Has a tumor that is dependent upon HRAS and/or PIK3CA.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  7. Acceptable liver, renal, endocrine, and hematologic function.
  8. Must be able to swallow alpelisib whole tablet or oral suspension containing crushed tablets. Feeding tube may not be used for alpelisib administration.
  9. Other protocol defined inclusion criteria may apply.

Exclusion Criteria:

  1. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (eg, mucosal melanoma).
  2. Ongoing treatment with certain anticancer agents.
  3. Prior treatment (at least 1 full treatment cycle) with an FTI or PI3K, mTOR, or AKT inhibitor.
  4. Received treatment for unstable angina, myocardial infarction, and/or cerebro-vascular attack within the prior 6 months.
  5. Non-tolerable Grade 2, or ≥ Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1.
  6. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery.
  7. Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy.
  8. Participant with an established diagnosis of diabetes mellitus Type 1 or not controlled Type 2.
  9. Participant has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drugs based on Investigator discretion.
  10. Participant has currently documented pneumonitis/interstitial lung disease.
  11. Participant has a history of severe cutaneous reaction, such as Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
  12. Other protocol defined exclusion criteria may apply.
Contacts and Locations
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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): NCT04997902


Contacts
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Contact: Clinical Operations 617-588-3755 KO-TIP-013@kuraoncology.com

Locations
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United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Khaleda Khan       kkhan@coh.org   
Principal Investigator: Victoria M Villaflor, MD         
United States, Florida
Lake Nona DDU (Florida Cancer Specialists) Recruiting
Orlando, Florida, United States, 32827
Contact: Cesar A Perez, MD    689-216-8500    Cesar.PerezBatista@flcancer.com   
Principal Investigator: Cesar A Perez, MD         
United States, Maryland
University of Maryland School of Medicine (Marlene and Stewart Greenebaum Comprehensive Cancer Center) Recruiting
Baltimore, Maryland, United States, 21201
Principal Investigator: Ranee Mehra, MD         
Johns Hopkins University School of Medicine (Sidney Kimmel Comprehensive Cancer Center) Recruiting
Baltimore, Maryland, United States, 21231
Contact: Tracey K Adams, RN, BA         
Contact: Peggy Fitzpatrick, MSN       mfitzpa7@jhmi.edu   
Principal Investigator: Tanguy Y Seiwert, MD         
United States, Massachusetts
Dana-Farber Cancer Institute (Head and Neck Cancer Treatment Center) Recruiting
Boston, Massachusetts, United States, 02215
Contact: Glenn J Hanna, MD    617-632-3090      
Principal Investigator: Glenn J Hanna, MD         
United States, Missouri
Washington University, School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Jessica Ley, MD    314-747-8092    jcley@wustl.edu   
Principal Investigator: Douglas R Adkins, MD         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Susan Korte       kortes@mskcc.org   
Principal Investigator: Alan L Ho, MD, PhD         
United States, Pennsylvania
UPMC Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Kasey Stragand, RN    412-647-9015    stragandk2@upmc.edu   
Principal Investigator: Dan P Zandberg, MD         
United States, Texas
UT Southwestern Medical Center (Harold C. Simmons Comprehensive Cancer Center) Recruiting
Dallas, Texas, United States, 75390
Contact: Tiffany Thomas, BSN, RN       tiffany.thomas@utsouthwestern.edu   
Principal Investigator: Randall S Hughes, MD         
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Jessie (Xiaoyan) Jia, MS RN OCN CCRP    (713) 792-9801    xjia1@mdanderson.org   
Principal Investigator: Maura L Gillison, MD, PhD         
United States, Wisconsin
University of Wisconsin Carbone Cancer Center Recruiting
Madison, Wisconsin, United States, 53792
Contact: Justine Y Bruce, MD    608-261-1500    lunggroup@uwcarbone.wisc.edu   
Principal Investigator: Justine Y Bruce, MD         
Sponsors and Collaborators
Kura Oncology, Inc.
More Information
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Responsible Party: Kura Oncology, Inc.
ClinicalTrials.gov Identifier: NCT04997902    
Other Study ID Numbers: KO-TIP-013
First Posted: August 10, 2021    Key Record Dates
Last Update Posted: August 30, 2022
Last Verified: August 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kura Oncology, Inc.:
HRAS
PIK3CA
PI3K
Tipifarnib
 Alpelisib
R/M HNSCC (Recurrent/metastatic Head and Neck Squamous Cell Carcinoma)
Head and Neck Cancer
SCCHN
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
 Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Tipifarnib
Antineoplastic Agents