Dose-Escalated Hypofractionated Adaptive Radiotherapy for Head and Neck Cancer

• Status: Recruiting
• Trial end date: 2022-12-01
• Target enrollment: 0
• Participant gender: All

Summary

Locoregional failure remains the principal mode of mortality in head and neck squamous cell carcinoma (HNSCC) treated with conventional chemoradiation therapy. Magnetic resonance-guided radiation therapy (MRgRT) allows for adaptive radiation dose escalation based on tumor response and may improve therapeutic outcomes while limiting toxicities.

This protocol evaluates a novel framework for radiation delivery with concurrent atezolizumab in patients with advanced HNSCC. Dose-Escalated Hypofractionated Adaptive Radiotherapy (DEHART) modifies radiation dose using MRgRT by escalating radiation dose to residual tumor while deescalating radiation dose to areas of tumor regression.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Medical College of Wisconsin
• Collaborator: Genentech, Inc.
• Treatments: Atezolizumab

Criteria

Inclusion Criteria:

• Age ≥18 years

• Diagnosis of T3-T4 N0-N3 M0 or T0-T4 N1-N3 M0 squamous cell carcinoma of the head and neck squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or carcinoma of unknown head/neck primary) based on American Joint Committee on Cancer guideline (AJCC; 8th edition) with measurable disease who meet at least 1 one of the following 3 criteria:

1. Not a candidates for concurrent, bolus, cisplatin-based chemoradiation therapy based on one of the following criteria (a-e)

1. Age ≥ 70 with moderate to severe comorbidity or vulnerability to cisplatin, defined as having one or more of the following conditions within 4 week of registration:

1. Modified Charlson Comorbidity Index ≥ 1

2. Adult Comorbidity Evaluation-27 (ACE-27) Index ≥ 1

3. ω score < 0.80

4. Geriatric 8 (G-8) score ≤ 14

5. Cancer and Aging Research Group (CARG) Toxicity Score ≥ 30%

6. Cumulative Illness Rating Scale-Geriatric (CIRS-G) Score ≥ 4

2. Age < 70 with severe comorbidity or vulnerability to cisplatin, defined as having two or more of the following conditions within 4 weeks prior to registration:

1. Modified Charlson Comorbidity Index ≥ 1

2. ACE-27 Index ≥ 1

3. ω score < 0.80

4. G-8 score ≤ 14

5. CARG Toxicity Score ≥ 30%

6. CIRS-G Score ≥ 4

3. Creatinine clearance < 60 cc/min by the Cockroft-Gault formula

4. Pre-existing peripheral neuropathy

5. Clinical need for a hearing aid or 25+ decibel shift over 2 contiguous frequencies on a pre-treatment hearing test

2. Patient refuses concurrent cisplatin-based chemoradiation therapy

3. Patient has recurrent disease after definitive surgical resection

• Any patient 18 years or older with primary metastatic (AJCC 8th edition T1-T4 N0-N3 M1) squamous cell carcinoma of the head and neck

• Zubrod performance status 0-3

• Measurable primary and/or nodal tumor in the head and neck region at the time of radiotherapy

• Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.

• Ability to tolerate multiple MRIs

• Adequate hematologic function within 14 days prior to registration defined as follows:

Absolute neutrophil count (ANC) ≥ 1,000 cells/mm^3, platelets ≥ 100,000 cells/mm^3, hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable).

• Adequate hepatic function within 14 days prior to registration defined as follows:

aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 times institutional upper limit of normal, serum bilirubin ≤ 1.5 x institutional upper limit of normal.

• For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to registration is required. Note: Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

• Inclusion of Covid-19 positive patients will be based on standard institutional protocol

Exclusion Criteria:

• Prior invasive malignancy within the past 3 years (except for non-melanomatous skin cancer, and early stage treated prostate cancer);

• Life expectancy less than 12 months

• Performance status Zubrod >3

• Inability to encompass all gross disease in 19 cm superior to inferior planning target volume to be treated on the MR LINAC

• MRI-incompatible foreign body

• Claustrophobia precluding ability to tolerate multiple MRIs

• MRI-incompatible pacemaker or implantable cardioverter defibrillator (ICD) placement

• Patients with Cochlear implant

• Patients with prior radiation therapy to the head and neck Note: Prior external beam radiotherapy is excluded, but Iodine 131 is allowed.

• Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune therapy for the study cancer

• Major surgery within 28 days prior to registration

• Body weight ≤ 30 kg

• Any of the following severe laboratory abnormalities within 14 days of registration, unless corrected prior to it: Sodium < 130 mmol/L or > 155 mmol/L; Potassium < 3.5 mmol/L or > 6 mmol/L ;Fasting glucose < 40 mg/dl or > 400 mg/dl;Serum calcium (ionized or adjusted for albumin) < 7 mg/dl or > 12.5 mg/dl; Magnesium < 0.9 mg/dl or > 3 mg/dl

• Unstable angina and/or congestive heart failure requiring hospitalization within 3 months prior to Step 1 registration

• Transmural myocardial infarction within 3 months prior to Step 1 registration

• Respiratory illness requiring hospitalization at the time of Step 1 registration

• Note: If the respiratory illness is resolved and the patient meets the eligibility status above, then the patient can be considered for the trial.

• Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to require oxygen therapy within 1 year prior to Step 1 registration

• History of (non-infectious) pneumonitis that required steroids or current pneumonitis

• Clinically apparent jaundice and/or known coagulation defects

• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: Patients with vitiligo or alopecia; Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; Any chronic skin condition that does not require systemic therapy; Patients without active disease in the last 5 years may be included but only after consultation with the medical oncology study chair; Patients with celiac disease controlled by diet alone.

• History of active primary immunodeficiency including, but not limited to Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition; Note: HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatment involved in this protocol may be immunosuppressive. Patients with known HIV, cluster of differentiation 4 (CD4) cell counts ≥ 200/μL, and undetectable viral loads who are stable on an antiretroviral regimen may be included.

• Current or prior use of immunosuppressive medication within 14 days before registration, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid

• Receipt of live attenuated vaccination within 30 days prior to registration

• Medical or psychiatric illness which would compromise the patient's ability to tolerate treatment or limit compliance with study requirements

• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 6 months after the last dose of atezolizumab, this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. Women who are breastfeeding are also excluded.

• Prior allergic reaction or hypersensitivity to atezolizumab or any of study drug excipients.

• History of allogenic organ transplantation

• Uncontrolled hypertension

• Uncontrolled cardiac arrhythmia

• Uncontrolled serious chronic gastrointestinal condition associated with diarrhea

• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing in line with local practice), hepatitis B (known positive hepatitis B viral (HBV) surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody (anti-HBc) and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.