CLR 131 Combined With Radiation for Head and Neck Cancer
CLR 131 Combined With Radiation for Head and Neck Cancer
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 24 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.
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.
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.