Tipifarnib + Alpelisib for Head and Neck Cancer

Recruiting at 10 trial locations

Overseen By Clinical Operations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Waitlist Available

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. ^{1 2 3 4 5}

Is 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. ^{1 2 4 5 6}

What 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. ^{1 5 7 8 9}

Eligibility 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.

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.

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

Treatment Details

Interventions

• Alpelisib (PI3K Inhibitor)
• Tipifarnib (Farnesyltransferase Inhibitor)

Trial Overview 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.

Participant Groups

Group I: PIK3CA-dependent (Cohort 1) Experimental Treatment 2 Interventions

Adult participants with R/M HNSCC whose tumors harbor PI3KCA (activating) mutations and/or amplifications

Group II: HRAS-dependent (Cohort 2) Experimental Treatment 2 Interventions

Adult participants with R/M HNSCC whose tumors have increased HRAS dependency, defined as HRAS overexpression

Who Is Running the Clinical Trial?

Kura Oncology, Inc.

Lead Sponsor

Trials

19

Recruited

1,700+

Findings from Research

The combination of tipifarnib and alpelisib shows promising efficacy in treating recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), particularly in patients with PIK3CA mutations or HRAS overexpression, potentially benefiting over 45% of these patients.

This treatment strategy works by targeting key cancer drivers and preventing resistance mechanisms, leading to significant tumor regression in preclinical models and supporting the launch of the KURRENT-HN trial to further evaluate its clinical effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity. Smith, AE., Chan, S., Wang, Z., et al.[2023]

In a phase 1b and phase 2 study involving patients with platinum-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), the combination of alpelisib and cetuximab showed an overall response rate of 25% and a disease control rate of 75% in the phase 1b study, indicating moderate anti-tumor activity.

While the combination treatment did not show a progression-free survival (PFS) benefit in cetuximab-naïve patients, it demonstrated moderate activity in cetuximab-resistant patients, with a median PFS of 3.9 months and a consistent safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1b/2 Study of Alpelisib in Combination with Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. Razak, ARA., Wang, HM., Chang, JY., et al.[2023]

Tipifarnib, when used alone, moderately inhibits tumor growth in head and neck squamous cell carcinoma (HNSCC) with wild-type H-Ras, but its effects are limited as a single agent.

Combining tipifarnib with the EGFR inhibitor cetuximab significantly enhances the anti-proliferative effects in both cell cultures and patient-derived xenograft models, suggesting a potential synergistic treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tipifarnib enhances anti-EGFR activity of cetuximab in non-HRas mutated head and neck squamous cell carcinoma cancer (HNSCC). Shu, L., Wang, D., Nannapaneni, S., et al.[2022]

In a phase II trial involving 41 patients with operable head and neck squamous cell carcinoma (HNSCC), preoperative treatment with olaparib, either alone or in combination with cisplatin or durvalumab, was found to be safe and resulted in a significant reduction in tumor cell proliferation, as indicated by a decrease in Ki67 of at least 25% in 44.8% of treated patients.

The treatment also modulated the tumor microenvironment, leading to increased levels of PD-L1 and changes in macrophage polarization, suggesting that combining olaparib with other therapies may enhance its antitumor effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Window Study of Olaparib Alone or with Cisplatin or Durvalumab in Operable Head and Neck Cancer. Moutafi, M., Koliou, GA., Papaxoinis, G., et al.[2023]

Tipifarnib has shown effectiveness in producing responses in patients with head-and-neck squamous-cell carcinoma (HNSCC), indicating its potential as a treatment option for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Farnesyltransferase Inhibitor Shows Efficacy in HRAS-Mutant HNSCC. [2021]

Prolonged treatment with the PI3Kα inhibitor alpelisib in head and neck squamous cell carcinoma (HNSCC) led to the upregulation of TYRO3 and AXL receptor tyrosine kinases, which are associated with acquired drug resistance.

Targeted knockdown of TYRO3 and AXL, as well as inhibition of MAPK signaling, successfully re-sensitized drug-resistant HNSCC cells to alpelisib, suggesting that combining pan-TAM inhibition with PI3Kα inhibitors could improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma. Ruicci, KM., Meens, J., Plantinga, P., et al.[2022]

In a phase 2 study involving 158 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, the combination of buparlisib (a pan-PI3K inhibitor) and paclitaxel significantly improved median progression-free survival to 4.6 months compared to 3.5 months with placebo plus paclitaxel, indicating enhanced clinical efficacy.

While the buparlisib group experienced a higher rate of grade 3-4 adverse events (82%) compared to the placebo group (72%), the safety profile was considered manageable, suggesting that buparlisib could be a viable second-line treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Soulières, D., Faivre, S., Mesía, R., et al.[2022]

Tipifarnib, a farnesyl transferase inhibitor, shows promising clinical activity in treating head and neck squamous cell carcinoma (HNSCC) with HRAS mutations, indicating its potential as a targeted therapy.

Recent analyses suggest that the HRAS pathway may be important in a wider range of squamous cell carcinomas, and tipifarnib could enhance the effectiveness of other treatments like cisplatin and cetuximab, making it a valuable option for combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas. Kessler, L., Malik, S., Leoni, M., et al.[2021]

In a pilot study involving 12 patients with recurrent and metastatic head and neck squamous cell carcinoma, the maximum tolerated dose of the PI3K inhibitor buparlisib was determined to be 100 mg daily when combined with cetuximab, and this combination was well-tolerated with no dose-limiting toxicities observed.

The combination treatment showed promising results, with one patient achieving a partial response and four others maintaining stable disease, indicating potential benefits for patients who had previously been treated with cetuximab alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Brisson, RJ., Kochanny, S., Arshad, S., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity. [2023]

2. France pubmed.ncbi.nlm.nih.gov

A Phase 1b/2 Study of Alpelisib in Combination with Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Tipifarnib enhances anti-EGFR activity of cetuximab in non-HRas mutated head and neck squamous cell carcinoma cancer (HNSCC). [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Phase II Window Study of Olaparib Alone or with Cisplatin or Durvalumab in Operable Head and Neck Cancer. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

A Farnesyltransferase Inhibitor Shows Efficacy in HRAS-Mutant HNSCC. [2021]

6. England pubmed.ncbi.nlm.nih.gov

TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma. [2022]

7. England pubmed.ncbi.nlm.nih.gov

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]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

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]