Tipifarnib + Alpelisib for Head and Neck Cancer

Not currently recruiting at 12 trial locations

Overseen By Clinical Operations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Kura Oncology, Inc.

Must not be taking: Anticancer agents

Disqualifiers: Diabetes, Pneumonitis, Neuropathy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: 6 cycles of 28 days each

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two drugs, tipifarnib (Zarnestra) and alpelisib (Piqray), to treat a specific type of head and neck cancer that has recurred or spread. The focus is on cancers linked to genetic changes involving the HRAS protein and PIK3CA gene. The trial includes two groups: one for tumors with PIK3CA changes and another for tumors with HRAS overexpression. Individuals who have experienced at least one failed treatment for this cancer and can swallow the medication might be suitable for this trial. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that tipifarnib is generally well-tolerated by patients with head and neck squamous cell carcinoma (HNSCC). In earlier studies, patients experienced expected side effects for this type of treatment, indicating a consistent safety profile for tipifarnib.

Similarly, alpelisib has demonstrated a reliable safety profile in people with various cancers, including HNSCC. The FDA has already approved it for another condition, confirming its known safety record. Many patients handled it well, although some experienced mild to moderate side effects.

Both tipifarnib and alpelisib have undergone extensive study. While side effects can occur, patients have generally received these treatments well in past studies. These findings may offer reassurance about the safety of these treatments for those considering joining this trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Tipifarnib and Alpelisib for head and neck cancer because these treatments target specific genetic mutations, offering a personalized approach. Tipifarnib focuses on tumors with HRAS overexpression, which is a new way to tackle cancer cells that rely heavily on the HRAS pathway. Meanwhile, Alpelisib targets PI3KCA mutations, which are key drivers in some head and neck cancers. Unlike standard treatments that might not consider these genetic factors, these drugs aim to stop cancer growth by directly interfering with the pathways that fuel it, potentially leading to more effective and tailored therapies.

What evidence suggests that this trial's treatments could be effective for head and neck cancer?

In this trial, participants will receive either Tipifarnib or Alpelisib, based on their tumor's genetic characteristics. Previous studies have shown that Tipifarnib benefits patients with head and neck squamous cell carcinoma (HNSCC) with HRAS mutations, extending the time without cancer progression to 5.6 months, compared to 3.6 months with earlier treatments. Participants in the HRAS-dependent cohort will receive Tipifarnib. Alpelisib, administered to participants in the PIK3CA-dependent cohort, has proven effective for patients with tumors exhibiting changes in the PI3K pathway. While the drug's effects vary with specific genetic changes in the tumor, it generally elicited a meaningful response. Both treatments target specific genetic mutations in cancer cells to slow or stop their growth. These findings suggest that both Tipifarnib and Alpelisib could be effective options for treating this type of cancer. ^{3 4 6 7 8}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Alpelisib
• Tipifarnib

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.

How Is the Trial Designed?

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

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

Who Is Running the Clinical Trial?

Kura Oncology, Inc.

Lead Sponsor

Trials

19

Recruited

1,700+

Published Research Related to This Trial

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]

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]

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 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]

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 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]

Citations

1. e-crt.org e-crt.org/journal/view.php?number=3725

Differential Efficacy of Alpelisib by PIK3CA Mutation Site in ... Alpelisib showed differential efficacy based on PI3K pathway alterations in patients with R/M HNSCC and was well-tolerated. These findings ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39901702/

Differential Efficacy of Alpelisib by PIK3CA Mutation Site in ... Alpelisib showed differential efficacy based on PI3K pathway alterations in patients with R/M HNSCC and was well-tolerated.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10663259/

A Phase 1b/2 Study of Alpelisib in Combination with ... Alpelisib–cetuximab achieved an overall response rate of 25% and 9.9% and disease control rate of 75% and 43.7% in phase 1b and phase 2 studies, ...

4. journals.lww.com journals.lww.com/jcrp/fulltext/2023/10020/promising_response_with_pi3k_inhibitor_for_a.6.aspx

Promising Response with PI3K Inhibitor for a Patient with... In the cohort of patients receiving alpelisib and fulvestrant, the median OS was 26.4 months and the median PFS was 7.3 months, with an ORR of 21.0%.

5. ir.kuraoncology.com ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-reports-preliminary-proof-mechanism-phase-12

Press Release The 35-year-old patient enrolled in KURRENT-HN after failing two prior treatments, experienced an 81% reduction in target lesions after one cycle of tipifarnib ...

6. eocco.com eocco.com/-/media/EOCCO/PDFs/Formulary/alpelisib_piqray.pdf

alpelisib (Piqray®, Vijoice®) Alpelisib (Piqray, Vijoice) is an orally administered kinase inhibitor with predominant activity against PIK3CA gene. It is FDA-approved for the treatment of ...

7. ema.europa.eu ema.europa.eu/fr/media/48505

Alpelisib EU Safety Risk Management Plan case each was reported in a subject with breast cancer, squamous cell carcinoma of head and neck, metastatic pancreatic neuroendocrine tumor ...

8. novartis.com novartis.com/us-en/sites/novartis_us/files/piqray.pdf

Piqray The safety of PIQRAY was evaluated in a randomized, double-blind, placebo-controlled trial (SOLAR-1) in 571 patients with HR-positive, HER2-negative, advanced ...