CLR 131 Combined With Radiation for Head and Neck Cancer

Study Overview
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Brief Summary
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This is a Phase 1 study of the use of an investigational drug that selectively delivers radiation to malignant tumor cells, CLR 131, in combination with external beam radiation therapy (EBRT) in subjects with locoregionally recurrent head and neck cancer. The trial will enroll up to 12 participants who are amenable to retreatment with radiation therapy. Participants who also have distant metastatic disease may be enrolled on this clinical trial, but they must have evaluable disease that will be clinically treated with radiation therapy, as per standard of care. All participants will receive a dosimetry test dose of CLR 131 to establish drug uptake by the tumor and enable Monte Carlo dose estimation based on CLR 131 SPECT/CT imaging evaluation. Participants showing uptake will receive a cumulative tumor dose of 60-70 Gy using personalized dose calculation (via Monte Carlo methods) of CLR 131 combined with external beam radiation.

Detailed Description
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Following informed consent, all participants will receive a dosimetry test dose of 15 mCi CLR 131 to establish drug uptake by the tumor and enable Monte Carlo dose estimation based on CLR 131 SPECT/CT imaging evaluation. Participants who have uptake of the CLR 131 dosimetry test dose at their disease site as determined by the study radiologist will be eligible to participate on the treatment portion of this clinical trial. Participants showing uptake will receive a cumulative tumor dose of 60-70 Gy using personalized dose calculation of CLR 131 (via Monte Carlo) combined with external beam radiation. In this study, we are also studying a subset of up to 6 patients who do not uptake after the CLR 131 test dose, who will still proceed with treatment with CLR 131. This clinical trial involves two cohorts of subjects: (a) dose escalation and (b) dose expansion. In the dose escalation phase, an mTPI-2 design, an extension of modified toxicity probability interval (mTPI-2), will be used to identify the maximum tolerated dose (MTD) using cohorts of 4 participants and up to 3 dose levels of CLR 131. Participants in the dose escalation phase will receive 2 doses of CLR 131 with the first dose on day 1 followed by the second dose on day 8. Treatment with CLR 131 on the dose escalation cohort will begin at dose level 1 (15.6 mCi/m2). Participants at dose level 1 will receive an intravenous infusion of CLR 131 at 15.6 mCi/m2 on day 1 followed by a second dose on day 8. Participants at dose level 2 will receive an intravenous infusion of CLR 131 at 18.75 mCi/m2 on day 1 followed by a second dose on day 8. Once the MTD is determined by the dose escalation phase, participants will be enrolled on the dose expansion cohort. Participants on the dose expansion cohort will receive 2 doses of CLR 131 with the first dose on day 1 followed by the second dose on day 8, with the dose determined by the dose escalation phase. SPECT/CT imaging will be performed on days 2, 3, 4-6, and 7-8 of the treatment period to visualize and quantitate the biodistribution of CLR 131. Based on these SPECT/CT imaging scans, the Bednarz lab will utilize the Monte Carlo method to predict absorbed dose of CLR 131 to tumors and normal structures. All participants will start thyroid-protection medication the day prior to the CLR 131 dosimetry test dose and will continue to take thyroid protection medication for 14 days after the last CLR 131 dose. Based on the calculated absorbed dose of CLR 131 to the specific targeted tissue, the participant will undergo external beam radiation therapy (EBRT) to complete the designated radiation dose outlined in the re-irradiation plan, as per standard of care. Prior to CLR 131 administration and at 3 and 6 months post EBRT, participants will be assessed for changes to swallow function. Prior to CLR 131 administration and at 3, 6 and 12 months post EBRT, quality of life measures and salivary characteristics will be assessed. The investigators anticipate the total study (baseline, CLR 131 administration, EBRT and 3, 6, 12 and 24 month follow up assessments) to take 27 months per participant.

Official Title
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Therapeutic Combination of CLR 131 With External Beam Radiation in Head and Neck Cancer

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: CLR 131


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be informed of the investigational nature of the study and must be able to sign a written informed consent. Participants with histologically or cytologically confirmed solid malignancy that has recurred in the head and neck (above the clavicles) region, e.g., participants with recurrent cutaneous squamous cell carcinoma, salivary gland tumors or esthesioneuroblastoma are eligible for this clinical trial. Participants must have undergone previous curative intent therapy, with radiation as a primary or adjuvant therapy. Participants may have distant metastatic disease, as long as the locoregional site of recurrence is deemed eligible for radiation therapy, and treatment of the loco-regional disease is deemed as taking precedence over treatment of the remaining systemic disease. Participants must have at least one evaluable (measurable or non-measurable) recurrent lesion that is amenable to radiation therapy. Participants must demonstrate uptake of CLR 131 via SPECT/CT imaging, as determined by the study radiologist, in the specified site of recurrent/metastatic disease that is to be treated with radiation therapy. There is a subset of up to 6 patients who may continue with CLR 131 treatment without uptake on the SPECT/CT scan after the test dose. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1. Participants must have a life expectancy of at least 6 months. The participant has adequate hematologic function, as evidenced by: an absolute neutrophil count (ANC) ≥ 1500 / µL hemoglobin ≥9 g/dL (5.58 mmol/L) and platelets ≥100,000 / µL If full-dose anticoagulation therapy is used, platelets ≥ 150,000 / µL are required. If participant is on full-dose anticoagulation therapy, the anticoagulation therapy must be reversible, and reversal of the anticoagulation therapy must not be life-threatening, as judged by the investigator. The participant has adequate renal function as defined by: serum creatinine ≤ 1.5 times the upper limit of normal (ULN) or Cockcroft-Gault calculated creatinine clearance >/= 60 ml/min The participant has adequate hepatic function as defined by: total bilirubin ≤ 1.5 mg/dL (25.65 μmol/L) aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 times the ULN Women of childbearing potential (WOCP) have a confirmed negative urine pregnancy test within 24 hours prior to test dose of CLR 131. Participants must use a medically acceptable method of birth control such as an oral, implantable, injectable, or transdermal hormonal contraceptive, an intrauterine device (IUD), a double barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total abstinence during the study participation and for 6 months after last dose of study drug. Women who are postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) are not considered to be WOCP. Men who are not surgically or medically sterile agree to use an acceptable method of contraception. Male participants with female sexual partners who are pregnant, possibly pregnant, or who could become pregnant during the study must abstain from intercourse for three weeks after each CLR 131 dose and agree to use condoms at least 6 months after the last dose of study drug. Total abstinence for the same study period is an acceptable alternative. Exclusion Criteria: Recurrent tumor recommended for surgical resection based on multidisciplinary Head and Neck Oncology Tumor Board Review Thyroid cancer Known hypersensitivity to iodine Other concurrent severe and/or uncontrolled concomitant medical or psychiatric conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol, per investigator discretion Chemotherapy or major surgery within 4 weeks, or radiotherapy within 2 weeks prior to test dose of CLR 131. Participants with clinically significant adverse events due to agents administered more than 4 weeks prior to test dose of CLR 131 (alopecia and fatigue excluded). Clinical significance to be determined by investigator. The participant is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 6 months after the last dose of trial treatment. Any ongoing or active infection, including active tuberculosis, hepatitis B or C, or known infection with the human immunodeficiency virus (HIV) Concurrent treatment with any other anti-cancer or investigational agents. Participants cannot be receiving concomitant chemotherapy, radiotherapy, experimental therapy or any other therapy not otherwise outlined by the trial for the purposes of anti-cancer treatment. Participants with a history of or concurrent second primary malignancy (stage III or IV) within 5 years to study enrollment are excluded. Participants with a history of prior invasive malignancy (except early-stage I or II non-melanomatous skin cancer, carcinoma in situ of the breast, cervical carcinoma in situ, stage I-II papillary thyroid cancer, or low or very low-risk prostate cancer which has been completely treated with surgery or radiation) treated within 2 years of study enrollment are excluded. Participants that have had total body or hemibody irradiation, or have had prior systemic radioisotope therapy (except for benign thyroid disease) Poor venous access and will be unable to receive study drug into a peripheral venous catheter. Significant traumatic injury within 6 weeks prior to enrollment Extradural tumor in contact with the spinal cord or tumor located where swelling in response to therapy may impinge upon the spinal cord Any history of cerebrovascular accident (CVA) or transient ischemic attack within 12 months prior to study entry History of myocardial infarction, ventricular arrhythmia, stable/unstable angina, symptomatic congestive heart failure, coronary/peripheral artery bypass graft or stenting or other significant cardiac disease within 6 months prior to study entry QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥480 ms. Any condition requiring the use of immunosuppression, excluding rheumatologic conditions treated with stable doses of corticosteroids (equivalent to £ prednisone 10 mg daily) Ongoing hemodialysis or peritoneal dialysis Poorly controlled severe Chronic Obstructive Pulmonary Disease (COPD) Uncontrolled hypothyroidism or hyperthyroidism Any medical condition that predisposes the subject to uncontrolled bleeding such as hemophilia, factor deficiencies, severe liver disease, or von Willebrand disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single center, dose escalation and dose expansion study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLR 131 Dose Escalation<br>Enrollment will start at dose level 1 (first 4 participants). Participants will receive 2 doses of CLR 131 intravenously with the first dose on day 1 followed by the second dose on day 8. Dose Level -1 (de-escalation dose, if toxicities warrant) = 12.5 mCi/m^2 Dose Level 1 (beginning dose) = 15.6 mCi/m^2 Dose Level 2 (escalation dose) = 18.75 mCi/m^2 Dose escalation will proceed with no limiting toxicities at each level (maximum of 8 participants at each dose level). With maximum tolerated dose confirmed, an expansion phase will proceed. | Drug: CLR 131<br>* CLR 131 is a radiopharmaceutical dosed intravenously over a period of approximately 30 minutes, dose will be based on total body surface area calculated from actual body weight and height<br>* Other names: I-131-CLR1404;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | Incidence of adverse events assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. | up to 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CLR 131 Tumor Uptake via SPECT/CT Imaging | Investigators will use SPECT/CT imaging scans to predict the adsorbed dose of CLR 131 to tumors with the Monte Carlo method. | Up to 8 days | 
| Median Radiation Treatment Time |  | up to 14 weeks | 
| Median Number of Dose Delays Due to Toxicity |  | up to 14 weeks | 
| Overall Response Rate (ORR) | ORR defined as the proportion of subjects who experience either a partial response or complete response within 6 months post completion of EBRT as measured by standard of care imaging (e.g. CT, MR, PET-MR). | up to 9 months | 
| Change in Swallow Function: DIGEST Scale | Swallow function assessed by Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale before and after treatment. The DIGEST scale cross references a clinician determined 'safety' grade with an 'efficiency' grade for an overall score between 0-4 where 0 is asymptomatic and 4 is life threatening. | up to 9 months | 
| Change in Quality of Life: MDADI Score | Quality of life assessed by MD Anderson Dysphagia Inventory score (MDADI) before and after treatment. MDADI is a 36-item self-assessment with global, emotional, functional, and physical sub-scales. Total possible composite score range is 20-100 where 20 is extremely low functioning and 100 is high functioning. | up to 15 months | 
| Change in Stimulated Salivary Flow | Change in Stimulated Salivary Flow before and after treatment (mL/min). | up to 9 months |