Testing the Addition of an Anti-Cancer Drug, Camonsertib, to Radiation Therapy for Recurrent Head and Neck Squamous Cell Carcinoma

Phase I Trial of ATR Inhibitor Camonsertib Combined With Stereotactic Body Radiation Therapy for Recurrent Head and Neck Squamous Cell Carcinoma

This phase I trial tests the safety, side effects, and best dose of camonsertib in combination with stereotactic body radiation therapy in controlling disease in patients with head and neck squamous cell cancer that has come back after a period of improvement (recurrent) or that cannot be removed by surgery (unresectable). Camonsertib may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for cell growth. Stereotactic body radiation therapy is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Giving camonsertib in combination with stereotactic body radiation therapy may help control disease in patients with recurrent or unresectable head and neck squamous cell cancers.

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of camonsertib with concurrent head and neck stereotactic body radiotherapy (SBRT) reirradiation for patients with recurrent head and neck squamous cell carcinoma (HNSCC).

II. To determine the recommended phase 2 dose (RP2D) of camonsertib in combination with concurrent SBRT in these patients.

SECONDARY OBJECTIVES:

I. To assess overall response rate within the radiation therapy field for patients treated with camonsertib and SBRT.

II. To assess progression-free survival (PFS) with camonsertib and SBRT in patients with recurrent or new primary HNSCC within a previously irradiated field.

EXPLORATORY OBJECTIVES:

I. To identify predictive biomarkers of response to camonsertib and SBRT, including, but not limited to genetic alterations of ATM and TP53, human papillomavirus (HPV) status, tumor mutational load, and circulating tumor deoxyribonucleic acid (DNA).

II. To characterize the pharmacokinetics (PK) of camonsertib.

OUTLINE: This is a dose-escalation study of camonsertib in combination with SBRT followed by a dose-expansion study.

Patients undergo 4 or 5 treatment fractions of SBRT twice weekly, 2-3 days apart between fractions, over 3 weeks. Patients receive camonsertib orally (PO) once daily (QD) on the day of and the day after each radiation therapy treatment. Patients also undergo positron emission tomography (PET)/computed tomography (CT) or CT and collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up at weeks 4, 5, 6, 7, 16, 29, 42, and 55.

Inclusion Criteria:

• Patients must have histologically confirmed recurrent or metachronous (second primary) unresectable head and neck squamous cell carcinoma involving the oral cavity, oropharynx, larynx, hypopharynx, and/or paranasal sinus, or cervical lymphadenopathy with unknown primary. Core needle biopsy (preferably at least three 18-gauge cores) or incisional biopsy is preferred over fine needle aspiration (FNA) for diagnosis of recurrent disease or new primary head and neck squamous cell carcinoma to provide sufficient tumor tissue for correlative studies. Unresectable refers both to patients who have declined surgery and patients deemed unresectable by otolaryngology. This includes patients for whom curative resection is medically contraindicated and/or would be associated with excessive surgical risk (as deemed by the consulting otolaryngologist) or undue surgical morbidity (e.g., total glossectomy, laryngectomy, and/or major resection requiring free flap reconstruction). There are no requirements related to prior systemic therapies that patients may have received

• Patients must have recurrent disease within a previously irradiated area (radiotherapy to dose ≥ 30 gray [Gy] and ≤ 80 Gy; in-field recurrence)

• Patients must have completed prior radiotherapy at least 6 months prior to enrollment. Due to safety concerns, reirradiation within less than 6 months to the head and neck is very rarely recommended per standard of care

• Patients must have measurable disease (at least one measurable lesion) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Baseline imaging must include neck CT (preferably contrast-enhanced) and chest CT or skullbase to midthigh PET/CT (preferably with contrast-enhanced neck CT if diagnostic contrast-enhanced neck CT not available). Patients who have undergone surgery aside from biopsy may be included if gross disease is present within the surgical resection bed or at another site

• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of camonsertib in combination with radiotherapy in patients < 18 years of age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

• Leukocyte count ≥ 3,000/mcL

• Absolute neutrophil count ≥ 1,500/mcL

• Platelets ≥ 100,000/mcL

• Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin dependency (within 7 days of assessment)

• Serum bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (if total serum bilirubin > 1.5 × institutional ULN, then direct bilirubin must be < ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 × institutional ULN

• Albumin > 2.5 mg/dL

• Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2

  • GFR can be measured directly or estimated using the site's institutional standards

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better

• Ability to take pills by mouth

• The effects of camonsertib on the developing human fetus are unknown. For this reason and because ATR inhibitors and radiation are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after completion of camonsertib administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1), with the exception of alopecia

• Patients who are receiving any other investigational agents for a current cancer diagnosis

• Patients with distant metastatic disease

• Patients who have received more than one prior course of head and neck radiotherapy overlapping the region to be treated with the current diagnosis of head and neck cancer

• Patients who have disease surrounding > 180 degrees of the carotid artery

• Patients with tumors invading the mandible or tumors with gross skin involvement (i.e., tumor ulceration through the skin)

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to camonsertib or radiation

• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous

• Pregnant women are excluded from this study because camonsertib is an ATR inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with camonsertib, breastfeeding should be discontinued if the mother is treated with camonsertib. These potential risks may also apply to other agents used in this study

• Patients diagnosed with scleroderma

• Concomitant use of strong CYP3A4/5 inhibitors and inducers, and strong P-gp and BCRP inhibitors

  • Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product