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Cisplatin

Ipatasertib

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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.

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.

Biopsy

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Positron Emission Tomography

Radiation Therapy

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Laila A. Gharzai

Christopher Lominska

Susanne M. Arnold

Ranee Mehra

Malcolm D. Mattes

Varinder Kaur

Erin R. Alesi

Malcolm D Mattes

This phase I/Ib trial tests the safety and best dose of ipatasertib in combination with the usual treatment approach using chemotherapy together with radiation therapy ("chemo-radiation") in patients with head and neck cancer. Ipatasertib is in a class of medications called protein kinase B (AKT) inhibitors. It may stop the growth of tumor cells and may kill them. Cisplatin which is a chemotherapy used in this trial is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Radiation therapy uses high energy to kill tumor cells and shrink tumors. Giving ipatasertib in combination with chemo-radiation may be better than chemo-radiation alone in treating patients with advanced head and neck cancer.

PRIMARY OBJECTIVE:

I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ipatasertib in combination with definitive chemoradiation in locally advanced head and neck squamous cell carcinoma (HNSCC) based on dose-limiting toxicities (DLTs).

SECONDARY OBJECTIVES:

I. To assess acute and late toxicities, based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

II. To assess long-term swallowing function, based on gastric tube dependency at 6 and 12 months that is different from baseline.

III. To determine duration and completion rate of prescribed radiation and chemotherapy.

IV. To determine pharmacokinetic profile of ipatasertib in combination with cisplatin and radiation therapy, based on peak and trough blood levels in patients administered ipatasertib orally.

V. To determine pharmacodynamic effects of ipatasertib at the MTD, based on pAKT, pS6 and pPRAS40 as markers of AKT pathway inhibition, and gamma-H2AX as a marker of radiosensitization.

VI. To observe and record anti-tumor activity (objective response rate) by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, locoregional control, relapse-free survival, and overall survival) of the combination of ipatasertib, cisplatin, and radiation therapy in patients with HNSCC.

VII. To correlate efficacy outcomes with tumor genotype, based on whole exome sequencing of pre-treatment biopsy specimens.

OUTLINE: This is a phase I, dose-escalation study of ipatasertib in combination with fixed-dose cisplatin and radiation therapy followed by a dose-expansion study.

DOSE ESCALATION:

Patients receive ipatasertib orally (PO) once daily (QD) or Monday, Wednesday, and Friday depending on dose level on days 1-28 of each cycle. Patients also receive cisplatin intravenously (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 radiation therapy (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 positron emission tomography (PET)/computed tomography (CT), CT, or magnetic resonance imaging (MRI) during screening, follow-up, and as clinically indicated. Patients undergo blood sample collection on trial.

DOSE EXPANSION:

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.

After completion of study treatment, patients are followed for 30 days and then every 3 months for up to 2 years.

Testing the Addition of Ipatasertib to Usual Chemotherapy and Radiation for Head and Neck Cancer

Phase I/Ib Study of AKT Inhibitor Ipatasertib With Chemoradiation for Locally Advanced Head and Neck Cancer

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Patients who receive at least 70% of the prescribed course of ipatasertib on radiation days will be evaluable for dose limiting toxicity assessment. After the escalation phase of the trial is completed, the MTD will be selected using the pooled-adjacent-violators algorithm, a type of isotonic regression, as specified in Liu and Yuan (2015).

Will be assessed according to Common Terminology Criteria for Adverse Events version 5.0. Toxicities occurring \> 90 days from the end of radiation will be considered late toxicities. This will include assessment of long-term swallowing function, based on gastric tube dependency at 6 and 12 months as compared to baseline due to the effects of the primary tumor. Descriptive statistics will be used to summarize these toxicities.

Descriptive statistics will also be used to summarize the duration and completion rate of prescribed radiation and chemotherapy.

Assessed based on Response Evaluation Criteria in Solid Tumors, as well as locoregional control, relapse-free survival, and overall survival. Two-sample t-test, Mann-Whitney U test, or log rank test will be used where appropriate to analyze the correlation between efficacy outcomes and pre-treatment genotypic abnormalities in the AKT pathway based on whole exome sequencing and PTEN immunohistochemistry (IHC).

Will be assessed using peak and trough blood levels in patients administered ipatasertib orally during weeks 2 and 3 of study treatment. The combined therapy will be compared to historical PK data for drug alone, in order to assess for a drug-drug interaction.

Based on pAKT, pS6 and PRAS40 as markers of AKT pathway inhibition, and gamma-H2AX as a marker of radiosensitization. Two-sample t-test and Mann-Whitney U test will be used where appropriate to compare values before and after the addition of ipatasertib to chemoradiation.

Two-sample t-test, Mann-Whitney U test, or log rank test will be used where appropriate to analyze the correlation between efficacy outcomes and pre-treatment genotypic abnormalities in the AKT pathway based on whole exome sequencing and PTEN IHC.

National Cancer Institute (NCI)

Spots Global Cancer Trial Database for locally advanced nasal cavity squamous cell carcinoma