Tipifarnib + Alpelisib for Head and Neck Cancer
Recruiting in Palo Alto (17 mi)
+10 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Kura Oncology, Inc.
Must not be taking: Anticancer agents
Disqualifiers: Diabetes, Pneumonitis, Neuropathy, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This trial tests a combination of two drugs, tipifarnib and alpelisib, in patients with advanced head and neck cancer that have specific genetic changes. The drugs aim to stop cancer growth by blocking essential enzymes. Tipifarnib is a farnesyl transferase inhibitor that has shown clinical activity in head and neck squamous cell carcinoma, particularly in tumors with HRAS mutations.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it does exclude those who are on certain anticancer agents. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drug combination Tipifarnib and Alpelisib for head and neck cancer?
Research shows that combining Tipifarnib and Alpelisib can effectively target specific cancer drivers in head and neck cancer, leading to tumor shrinkage in lab and animal studies. This combination may help more than 45% of patients with certain genetic profiles of this cancer.
12345Is the combination of Tipifarnib and Alpelisib safe for humans?
The combination of Tipifarnib and Alpelisib has been studied for head and neck cancer, showing potential benefits and tumor regression in some cases. However, specific safety data for this combination in humans is not detailed in the available research, so it's important to discuss potential risks with your healthcare provider.
12456What makes the drug combination of Tipifarnib and Alpelisib unique for head and neck cancer?
This drug combination targets specific genetic drivers in head and neck cancer, namely PI3K-mTOR and HRAS, which are not typically addressed by standard treatments. Tipifarnib and Alpelisib work together to block pathways that help cancer cells survive, potentially benefiting a significant portion of patients with recurrent or metastatic head and neck cancer.
15789Eligibility Criteria
Adults over 18 with recurrent/metastatic head and neck squamous cell carcinoma not suitable for curative surgery or radiation. Must have failed at least one systemic therapy, have an ECOG performance status of 0-1, measurable disease by RECIST v1.1, HRAS-dependent and/or PIK3CA-mutated/amplified tumors, good organ function, and be able to swallow medication.Inclusion Criteria
My previous cancer treatment did not work as expected.
Other protocol defined inclusion criteria may apply
My tumor is driven by HRAS or PIK3CA mutations.
+6 more
Exclusion Criteria
I have completed at least one treatment cycle with specific cancer growth inhibitors.
I have a GI condition that could affect how my body absorbs medication.
My cancer originates from the salivary gland, thyroid, or skin.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive combination therapy of tipifarnib and alpelisib. DLTs are evaluated during the first 28 days (1 cycle) of combination therapy.
6 cycles of 28 days each
Blood samples collected on day 1 and day 2 of Cycle 1 and Cycle 2, and on day 1 of Cycle 3 through Cycle 6
Follow-up
Participants are monitored for safety and effectiveness after treatment, including overall survival and progression-free survival.
Up to approximately 3 years
Participant Groups
The trial is testing a combination of two drugs: Tipifarnib (a farnesyltransferase inhibitor) and Alpelisib (a PI3K inhibitor), in patients whose tumors overexpress the HRAS protein or are PIK3CA-mutated/amplified. It's a phase 1/2 study which means it's looking at safety as well as efficacy.
2Treatment groups
Experimental Treatment
Group I: PIK3CA-dependent (Cohort 1)Experimental Treatment2 Interventions
Adult participants with R/M HNSCC whose tumors harbor PI3KCA (activating) mutations and/or amplifications
Group II: HRAS-dependent (Cohort 2)Experimental Treatment2 Interventions
Adult participants with R/M HNSCC whose tumors have increased HRAS dependency, defined as HRAS overexpression
Alpelisib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Piqray for:
- Hormone receptor-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen
🇪🇺 Approved in European Union as Piqray for:
- Hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer in combination with fulvestrant
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Lake Nona DDU (Florida Cancer Specialists)Orlando, FL
Johns Hopkins University School of Medicine (Sidney Kimmel Comprehensive Cancer Center)Baltimore, MD
City of Hope Comprehensive Cancer CenterDuarte, CA
University of Texas MD Anderson Cancer CenterHouston, TX
More Trial Locations
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Who Is Running the Clinical Trial?
Kura Oncology, Inc.Lead Sponsor
References
Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity. [2023]Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility.
A Phase 1b/2 Study of Alpelisib in Combination with Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. [2023]Alpelisib in combination with cetuximab showed synergistic anti-tumour activity in head and neck squamous cell carcinoma (HNSCC) models.
Tipifarnib enhances anti-EGFR activity of cetuximab in non-HRas mutated head and neck squamous cell carcinoma cancer (HNSCC). [2022]To test the potential ability of tipifarnib to impair proliferation and to enhance the activity of the EGFR inhibitor cetuximab in wild-type H-Ras HNSCC, which accounts for the majority of HNSCC.
Phase II Window Study of Olaparib Alone or with Cisplatin or Durvalumab in Operable Head and Neck Cancer. [2023]We conducted a phase II randomized noncomparative window of opportunity (WOO) trial to evaluate the inhibition of cellular proliferation and the modulation of immune microenvironment after treatment with olaparib alone or in combination with cisplatin or durvalumab in patients with operable head and neck squamous cell carcinoma (HNSCC).
A Farnesyltransferase Inhibitor Shows Efficacy in HRAS-Mutant HNSCC. [2021]Tipifarnib produced responses in patients with head-and-neck squamous-cell carcinoma (HNSCC).
TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma. [2022]Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs).
Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. [2022]Phosphatidylinositol 3-kinase (PI3K) pathway activation in squamous cell carcinoma of the head and neck contributes to treatment resistance and disease progression. Buparlisib, a pan-PI3K inhibitor, has shown preclinical antitumour activity and objective responses in patients with epithelial malignancies. We assessed whether the addition of buparlisib to paclitaxel improves clinical outcomes compared with paclitaxel and placebo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas. [2021]Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis for exploration of combination approaches to drive better patient outcomes. Tipifarnib, a farnesyl transferase inhibitor (FTI), is a small molecule drug that has demonstrated encouraging clinical activity in a genetically-defined subset of head and neck squamous cell carcinoma (HNSCC)-specifically, tumors that express a mutation in the HRAS protooncogene. More recently, bioinformatic analyses and results from patient-derived xenograft modeling indicate that HRAS pathway dependency may extend to a broader subpopulation of SCCs beyond HRAS mutants in the context of combination with agents such as cisplatin, cetuximab, or alpelisib. In addition, tipifarnib can also inactivate additional farnesylated proteins implicated in resistance to approved therapies, including immunotherapies, through a variety of distinct mechanisms, suggesting that tipifarnib could serve as an anchor for combination regimens in SCCs and other tumor types.
A pilot study of the pan-class I PI3K inhibitor buparlisib in combination with cetuximab in patients with recurrent or metastatic head and neck cancer. [2022]This study assessed the maximum tolerated dose (MTD) of the PI3K inhibitor buparlisib given concurrently with cetuximab in recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).