Ipatasertib + Chemoradiation for Head and Neck Cancer

Recruiting at 16 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must be taking: Cisplatin

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Diabetes requiring insulin, Lung disease, others

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

Compensation: Varies

Number of Visits: 4

46 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests the safety and best dose of ipatasertib combined with chemo-radiation in patients with advanced head and neck cancer. Ipatasertib may help stop or kill cancer cells by blocking a protein they need to grow. The goal is to see if this combination works better than chemo-radiation alone.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use strong inhibitors or inducers of CYP3A4 or P-glycoprotein within 2 weeks before starting the study drug. It's important to discuss your current medications with the study team to avoid any potential interactions.

What data supports the effectiveness of the treatment Ipatasertib + Chemoradiation for Head and Neck Cancer?

Research shows that combining cisplatin with radiation therapy is a standard and effective treatment for advanced head and neck cancers, improving survival rates. Additionally, new agents like Ipatasertib, when combined with radiotherapy, may enhance treatment effectiveness due to their radiopotentiating properties, although specific data on Ipatasertib is not provided. ^{1 2 3 4 5}

Is the combination of Ipatasertib and chemoradiation safe for head and neck cancer treatment?

Cisplatin, a component of the treatment, is known to cause hearing loss and other side effects, but alternatives like carboplatin have less toxicity. Long-term studies show that cisplatin-based treatments can have significant side effects, but they are commonly used due to their effectiveness. ^{6 7 8 9 10}

What makes the Ipatasertib + Chemoradiation treatment unique for head and neck cancer?

This treatment combines Ipatasertib, a drug that targets specific cancer cell pathways, with standard chemoradiation (using cisplatin and radiation therapy), potentially offering a novel approach for patients who may not tolerate traditional cisplatin-based therapies. ^{2 4 7 11 12}

Research Team

Malcolm D Mattes

Principal Investigator

University Health Network Princess Margaret Cancer Center LAO

Eligibility Criteria

Adults with advanced head and neck cancer who can swallow tablets, have no prior treatment for their current cancer, and meet certain health criteria. They must not be pregnant or breastfeeding, have serious liver disease, uncontrolled illnesses like infections or diabetes requiring insulin, nor a history of allergic reactions to similar drugs.

Inclusion Criteria

Your blood sugar levels when fasting should be less than or equal to 150 mg/dL, and your HbA1c level should be less than or equal to 7.5%.

I can swallow pills.

I had hepatitis C but my recent tests show no virus.

Exclusion Criteria

My cancer originates from the nasopharynx, salivary, thyroid, parathyroid glands, or skin.

I do not have any uncontrolled illnesses or active infections.

I have a condition that affects how my body absorbs food.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Dose Escalation

Patients receive ipatasertib orally and cisplatin intravenously, with radiation therapy daily for 35 fractions over 7 weeks. Treatment repeats every 28 days for 2 cycles.

8 weeks

Daily visits for radiation therapy, weekly visits for chemotherapy

Dose Expansion

Patients receive ipatasertib at the maximum tolerated dose, with cisplatin and radiation therapy as in dose escalation. Treatment repeats every 28 days for 2 cycles.

8 weeks

Daily visits for radiation therapy, weekly visits for chemotherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with imaging and blood sample collection.

Up to 2 years

Every 3 months

Treatment Details

Interventions

• Cisplatin
• Ipatasertib
• Radiation Therapy

Trial Overview The trial is testing the safety and optimal dose of Ipatasertib when added to standard chemo-radiation therapy in treating head and neck cancers. It compares the effects of this combination against usual treatments alone to see if it's more effective in stopping tumor growth.

Participant Groups

Group I: Dose Expansion (ipatasertib, cisplatin, radiation therapy) Experimental Treatment 8 Interventions

Patients receive ipatasertib PO MTD on days 2-28 or 3-28 of cycle 1 and 1-28 of subsequent cycles. Patients also receive cisplatin IV weekly on day 1 of cycle 1, weeks 1-4 and day 1 of cycle 2, weeks 1-3 for 7 doses. Patients undergo RT daily (Monday-Friday) for 35 fractions during weeks 1-7. Treatment repeats every 28 days for a total of 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET/CT, CT, or MRI during screening, follow-up, and as clinically indicated. Patients undergo blood sample collection and tumor biopsy on trial.

Group II: Dose Escalation (ipatasertib, cisplatin, radiation therapy) Experimental Treatment 7 Interventions

Patients receive ipatasertib PO QD or Monday, Wednesday, and Friday depending on dose level on days 1-28 of each cycle. Patients also receive cisplatin IV weekly on day 1 of cycle 1, weeks 1-4 and day 1 of cycle 2, weeks 1-3 for 7 doses. Patients undergo RT daily (Monday-Friday) for 35 fractions during weeks 1-7. Treatment repeats every 28 days for a total of 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET/CT, CT, or MRI during screening, follow-up, and as clinically indicated. Patients undergo blood sample collection on trial.

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase II trial involving 32 patients with advanced head and neck cancer, the aggressive combination of cisplatinum and paclitaxel with hyperfractionated-accelerated radiotherapy resulted in a 5-year overall survival rate of 48% and a disease-free survival rate of 43%.

While the treatment showed promising response rates, with 69% achieving a complete response, it was associated with significant acute toxicities, including high rates of grade 3 mucositis (71%) and erythema (28%), indicating the need for extensive supportive care during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of a simultaneous radiochemotherapy with cisplatinum and paclitaxel in combination with hyperfractionated-accelerated radiotherapy in locally advanced head and neck tumors. Kuhnt, T., Becker, A., Bloching, M., et al.[2022]

Carboplatin-based chemoradiation therapy (CTRT) is a well-tolerated alternative for patients with locally advanced head and neck cancers who are unfit for cisplatin, with 84.1% of patients completing the planned treatment.

The study found a median overall survival of 28 months and progression-free survival of 17 months, suggesting that carboplatin-based CTRT may offer better outcomes compared to radical radiotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin-based concurrent chemoradiation therapy in locally advanced head and neck cancer patients who are unfit for cisplatin therapy. Noronha, V., Sharma, V., Joshi, A., et al.[2018]

In a study of 60 patients with locally advanced head and neck squamous cell carcinoma (HNSCC), weekly low-dose cisplatin (30 mg/m2) resulted in significantly lower acute toxicities compared to high-dose cisplatin (100 mg/m2 every 3 weeks), with 56.6% of patients experiencing severe side effects versus 76.6% in the high-dose group.

While the low-dose regimen had better patient compliance (70% completing at least 6 doses) and lower toxicity, it also resulted in a lower loco-regional control rate (57.6%) compared to the high-dose group (72.8%), indicating a trade-off between safety and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin Weekly Versus Every 3 Weeks Concurrently with Radiotherapy in the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinomas: What Is the Best Dosing and Schedule? Mashhour, K., Hashem, W.[2020]

Chemotherapy, particularly when combined with radiotherapy, is crucial for managing head and neck cancers in patients with potentially curable disease.

New chemotherapy agents like paclitaxel or docetaxel combined with gemcitabine and cisplatin or carboplatin show promise and should be evaluated in phase III trials against traditional regimens, especially for their ability to enhance the effects of radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New cytostatic agents for the treatment of head and neck cancer. Devriendt, D., Klastersky, J.[2022]

In a Phase III trial involving 308 patients with unresectable squamous cell head-and-neck carcinoma, adding weekly cisplatin to daily radiation therapy did not significantly improve overall survival or failure-free survival, indicating limited efficacy of this combination treatment.

While low-dose weekly cisplatin showed some potential for enhancing the effects of radiation therapy, it also increased the risk of late toxicities, particularly esophageal and laryngeal complications, suggesting a need for careful consideration of its use in treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III study of radiation therapy with or without cis-platinum in patients with unresectable squamous or undifferentiated carcinoma of the head and neck: an intergroup trial of the Eastern Cooperative Oncology Group (E2382). Quon, H., Leong, T., Haselow, R., et al.[2021]

In a study of 181 patients with locally advanced head and neck cancers, nimotuzumab-based concurrent chemoradiotherapy resulted in the least hematological toxicities compared to cisplatin, nedaplatin, and lobaplatin.

Lobaplatin was associated with a higher incidence of severe leukopenia (48.5%) and thrombocytopenia compared to cisplatin, indicating that while some alternatives to cisplatin may reduce gastrointestinal and nephrotoxicity, they can still pose significant hematological risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematological Toxicities of Concurrent Chemoradiotherapies in Head and Neck Cancers: Comparison Among Cisplatin, Nedaplatin, Lobaplatin, and Nimotuzumab. Wu, Q., Zhu, C., Zhang, S., et al.[2022]

In a phase II trial involving 32 patients with recurrent or metastatic head and neck squamous cell carcinoma, the combination of carboplatin and raltitrexed demonstrated moderate efficacy, with a 22% partial response rate and a median survival duration of 9.8 months.

The treatment was generally safe, with manageable toxicity; however, 25% of patients experienced severe neutropenia, and one patient dropped out due to persistent hepatic toxicity, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin in combination with raltitrexed in recurrent and metastatic head and neck squamous cell carcinoma: A multicentre phase II study of the Gruppo Oncologico Dell'Italia Meridionale (G.O.I.M.). Galetta, D., Giotta, F., Rosati, G., et al.[2014]

In a phase III trial involving 237 patients with inoperable head and neck cancer, intra-arterial (IA) cisplatin did not show improved tumor control compared to intravenous (IV) cisplatin, despite a higher dose being administered via IA.

Patients receiving IV cisplatin experienced worse late dysphagia, indicating a potential safety concern with IV administration, while overall survival and locoregional control were similar between both treatment methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late follow-up of the randomized radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) trial for advanced head and neck cancer. Heukelom, J., Lopez-Yurda, M., Balm, AJ., et al.[2018]

Pemetrexed shows promising efficacy as a treatment for head and neck cancer, particularly when used in combination with other chemotherapeutic agents or radiotherapy, based on a review of ten studies.

The drug has an acceptable safety profile, with fewer severe nonhematologic toxicities compared to cisplatin, making it a potential alternative worth further investigation, especially as a radiosensitizer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed in head and neck cancer: a systematic review. Argiris, A., Pennella, E., Koustenis, A., et al.[2018]

In a study of 89 head and neck cancer patients treated with cisplatin, 29% experienced moderate to severe hearing loss, particularly at higher frequencies, indicating significant ototoxicity associated with this chemotherapy.

Specific genetic variants related to drug metabolism and DNA repair were found to increase the risk of ototoxicity, with some patients having up to 32 times higher odds of severe hearing loss, suggesting these genetic markers could help predict who is at greater risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Clinical Aspects and Genetic Variants with the Severity of Cisplatin-Induced Ototoxicity in Head and Neck Squamous Cell Carcinoma: A Prospective Cohort Study. Macedo, LT., Costa, EFD., Carvalho, BF., et al.[2023]

In a study of 1,149 patients with advanced head and neck squamous cell carcinoma, carboplatin-based chemoradiotherapy showed similar cancer-specific mortality rates compared to cisplatin-based therapy, indicating that carboplatin can be an effective alternative for patients unable to receive cisplatin.

Both carboplatin and cisplatin-based chemoradiotherapy were found to be more effective than radiation therapy alone or radiation with cetuximab, suggesting that carboplatin should be further investigated as a viable treatment option for certain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival After Definitive Chemoradiotherapy With Concurrent Cisplatin or Carboplatin for Head and Neck Cancer. Xiang, M., Colevas, AD., Holsinger, FC., et al.[2020]

In a phase II study involving 23 patients with head and neck cancer, the combination of paclitaxel and cisplatin resulted in a partial response rate of 32% among evaluable patients, indicating some efficacy.

Despite the observed responses, the significant toxicity, including high rates of asthenia (56%) and other side effects, suggests that this chemotherapy regimen may not be suitable for palliative treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biweekly paclitaxel and cisplatin in patients with advanced head and neck carcinoma. A phase II trial. Licitra, L., Capri, G., Fulfaro, F., et al.[2020]

References

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

Phase II trial of a simultaneous radiochemotherapy with cisplatinum and paclitaxel in combination with hyperfractionated-accelerated radiotherapy in locally advanced head and neck tumors. [2022]

2. India pubmed.ncbi.nlm.nih.gov

Carboplatin-based concurrent chemoradiation therapy in locally advanced head and neck cancer patients who are unfit for cisplatin therapy. [2018]

3. Thailand pubmed.ncbi.nlm.nih.gov

Cisplatin Weekly Versus Every 3 Weeks Concurrently with Radiotherapy in the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinomas: What Is the Best Dosing and Schedule? [2020]

4. Belgium pubmed.ncbi.nlm.nih.gov

New cytostatic agents for the treatment of head and neck cancer. [2022]

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

Phase III study of radiation therapy with or without cis-platinum in patients with unresectable squamous or undifferentiated carcinoma of the head and neck: an intergroup trial of the Eastern Cooperative Oncology Group (E2382). [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Hematological Toxicities of Concurrent Chemoradiotherapies in Head and Neck Cancers: Comparison Among Cisplatin, Nedaplatin, Lobaplatin, and Nimotuzumab. [2022]

7. Greece pubmed.ncbi.nlm.nih.gov

Carboplatin in combination with raltitrexed in recurrent and metastatic head and neck squamous cell carcinoma: A multicentre phase II study of the Gruppo Oncologico Dell'Italia Meridionale (G.O.I.M.). [2014]

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

Late follow-up of the randomized radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) trial for advanced head and neck cancer. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Pemetrexed in head and neck cancer: a systematic review. [2018]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Association of Clinical Aspects and Genetic Variants with the Severity of Cisplatin-Induced Ototoxicity in Head and Neck Squamous Cell Carcinoma: A Prospective Cohort Study. [2023]

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

Survival After Definitive Chemoradiotherapy With Concurrent Cisplatin or Carboplatin for Head and Neck Cancer. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Biweekly paclitaxel and cisplatin in patients with advanced head and neck carcinoma. A phase II trial. [2020]