Iopofosine Plus EBRT Produces Remissions, Proves Safe in Recurrent/Metastatic Head and Neck Cancer

The addition of iopofosine I 131 (CLR 131) to external beam radiation therapy (EBRT) elicited a 64% complete remission (CR) rate and was well tolerated in patients with locoregionally recurrent/metastatic head and neck cancer, according to data from an investigator-initiated phase 1 trial (NCT04105543).^1,2

Findings presented at the 2024 Multidisciplinary Head and Neck Cancers Symposium showed that patients evaluable for efficacy (n = 11) achieved an overall response rate (ORR) of 73%. One patient (9%) experienced partial remission, and the rates of stable disease and progressive disease were 9% and 18%, respectively. The 1-year progression-free survival (PFS) and overall survival (OS) rates were 36% and 72%, respectively.¹

In the safety population (n = 12), any-grade treatment-related adverse effects (TRAEs) occurred in 92% of patients. The most common any-grade TRAEs consisted of thrombocytopenia (92%), anemia (92%), lymphopenia (75%), and neutropenia (75%). Grade 3 or higher TRAEs included thrombocytopenia (75%), lymphopenia (75%), neutropenia (67%), anemia (42%), febrile neutropenia (17%), and oral mucositis (8%).

“The study results underscore an important quality of iopofosine to safely combine with EBRT and enhance therapeutic effect without significantly increasing toxicity of treatment,” Andrei Shustov, MD, medical senior vice president of Cellectar Biosciences, stated in a news release.² “The durability of responses demonstrated by impressive PFS and OS in this patient population suggests that the combination of iopofosine and EBRT may target the primary tumor as well as micrometastatic disease beyond the conventional radiation field. This might result in synergistic therapeutic benefit applicable to a variety of solid tumors.”

Iopofosine in a novel, targeted small molecule phospholipid ether drug conjugate designed to selectively deliver I-131 to tumor cells via specialized cellular lipid rafts.¹

The single-center, phase 1 study conducted at Carbone Cancer Center of the University of Wisconsin School of Medicine and Public Health in Madison included patients at least 18 years of age with a histologically or cytologically confirmed solid malignancy that recurred in the head and neck region, including recurrent cutaneous squamous cell carcinoma, salivary gland tumors, or esthesioneuroblastoma. Patients with metastatic disease were allowed to enroll if the locoregional site of recurrence was deemed eligible for radiation therapy and treatment of locoregional disease took precedence vs treatment for remaining systemic disease.³

Prior curative intent therapy with radiation as a primary or adjuvant therapy was required. Other key inclusion criteria included at least 1 evaluable recurrent lesion amenable to radiation; an ECOG performance status of 0 or 1; a life expectancy of at least 6 months; and adequate hematologic, renal, and hepatic function.

Patients were excluded if they had a recurrent tumor recommended for surgical resection per multidisciplinary tumor board review; had thyroid cancer; had a known hypersensitivity to iodine; underwent chemotherapy or major surgery within 4 weeks of first study treatment; or received radiotherapy within 2 weeks of a test dose of iopofosine.

Patients were required to exhibit uptake of iopofosine via single-photon emission computed tomography (SPECT) or standard CT imaging, per study radiologist assessment, in the specified site of recurrent/metastatic disease intended to be treated with radiation. Notably, a subset of up to 6 patients were allowed to continue treatment with iopofosine without uptake imaging after the test dose.

The test dose was given between days –14 and –7, and good vs poor uptake of iopofosine was determined on or around day 3 and/or day 7 following the test dose. Eligible patients then received iopofosine on day 1 and day 8 at 15.6 mCi/m² (dose level 1) or 18.75 mCi/m² (dose level 2). SPECT/CT imaging occurred between doses, and the Monte Carlo method was used to calculate the absorbed dose of the agent. From days 15 to 85, patients then received EBRT at a total radiation dose ranging from 60 Gy to 70 Gy.¹

Safety served as the trial’s primary end point. Secondary end points comprised iopofosine uptake, radiation treatment time, dose delays due to toxicity, ORR, change in swallow function, change in quality of life, and change in stimulated salivary flow.³

In the safety population, the median age was 65.5 years (range, 47-84). All patients were White and non-Hispanic, and the majority of patients were male (75%). Seventy-five percent of patients had an ECOG performance status of 0.¹

Primary tumor site consisted of oropharynx (42%), nasopharynx (8%), larynx (8%), oral cavity (33%), and salivary gland (8%). Half of all patients had T1/T2 disease, and half of patients had N0/N1 disease. Disease stage per the eighth edition of American Joint Committee on Cancer staging manual included I (17%), II (25%), III (25%), IVA (17%), and IVB (17%).

At diagnosis, initial treatments included surgical resection (58%) and definitive chemoradiation (42%). Of the 7 patients who underwent surgery as initial treatment, 33% had adjuvant radiation, 17% had adjuvant chemoradiation, and 8% received no adjuvant treatment. At enrollment, 50% of patients were in first recurrence, and the other half had multiple recurrences. Notably, 1 patient had metastatic disease.

Sixteen patients consented to enroll in the study; however, only 12 patients received treatment. Reasons for withholding treatment included insufficient uptake of the test dose of iopofosine (n = 2) and rapidly progressing disease (n = 2).

Other any-grade TRAEs reported during the study included fatigue (50%); dry mouth (25%); oral/oropharyngeal pain (25%); febrile neutropenia (17%); oral mucositis (17%); anorexia (17%); dysphagia (17%); and weight loss (17%).

Lead study author Justine Yang Bruce, MD, of the University of Wisconsin, and colleagues, concluded that a fixed fractionated dose of iopofosine at 15.6 mCi/m² plus EBRT warrants further investigation in this patient population.

“In addition to positive data previously reported in hematologic malignancies including recent results from our pivotal [phase 2] CLOVER WaM study [NCT02952508] in Waldenström macroglobulinemia, these data further demonstrate iopofosine’s broad clinical activity in solid tumors,” James Caruso, president and chief executive officer of Cellectar Biosciences, added in a news release. “We are clearly pleased with these results which remain consistent with prior reported data demonstrating deep and durable responses with iopofosine treatment, including complete remissions, in a wide spectrum of malignancies.”

References

1. Bruce JY, Burr A, Kimple RJ, et al. Safety and toxicity of iopofosine I-131 with external beam radiation therapy (EBRT) in recurrent or metastatic head and neck cancer (HNC): results of a phase 1 study. Presented at: 2024 Multidisciplinary Head and Neck Cancers Symposium; February 29-March 2, 2024; Phoenix, AZ. Poster 149.
2. Cellectar Biosciences reports high rate of complete remission in investigator initiated phase I study of iopofosine in combination with external beam radiotherapy in recurrent head and neck cancer. News release. Cellectar Biosciences. March 4, 2024. Accessed March 4, 2024. https://www.cellectar.com/news-media/press-releases/detail/328/cellectar-biosciences-reports-high-rate-of-complete
3. CLR 131 combined with radiation for head and neck cancer. ClinicalTrials.gov. Updated January 25, 2024. Accessed March 4, 2024. https://clinicaltrials.gov/study/NCT04105543