Clinical Trials of Systemic Targeted Radionuclide Therapies

382. Clinical Trials of Systemic Targeted Radionuclide Therapies

Only Fast-Track proposals will be accepted.

Number of Anticipated Awards: 2-4

Budget (total costs, per award):  Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

This topic calls for “first in human” studies and Phase I/II clinical trials of targeted radionuclide therapy (TRT) for cancer using novel radiopharmaceuticals or TRT treatment strategies as described in the project goals below.

TRT enables personalized cancer treatment by combining the therapeutic effect of radiation therapy with the targeting capability of molecularly targeted agents, such as antibodies used for biologically targeted therapy or immunotherapy. In TRT, a cytotoxic dose of a radioactive isotope is attached to a tumor-targeting agent that binds to malignant tumor cells selectively. For instance, the ability of the antibody to bind only to a tumor-associated antigen ensures that the tumor gets a lethal dose of radiation, while normal tissue gets only a minimal dose. This minimizes toxicity to normal tissues and can increase therapeutic efficacy (therapeutic index).

The first clinical application of TRT was the treatment of thyroid cancer with radioactive iodine, and the field of TRT has since expanded with clinically approved indications for non-Hodgkin lymphoma, bone metastases, and neuroendocrine tumors including neuroblastoma. Two radioimmunotherapy agents involving ⁹⁰Y- and ¹³¹I-labeled CD20 (Bexxar and Zevalin) were approved for the treatment of non-Hodgkin lymphoma, but their clinical use has been limited due to lack of coordination between nuclear medicine physicians and oncologists, concerns about radiation safety, and issues surrounding reimbursement. Building on the prior success of ⁸⁹Sr and ¹⁵³Sm, ²²³RaCl₂ (Xofigo) was shown to improve survival for men with bone metastases from castration-resistant prostate cancer and has reinvigorated interest in the development of novel TRT agents. Most recently, ¹⁷⁷Lu-dotatate (Lutathera) has been approved by FDA for treatment of neuroendocrine tumors.

As this class of treatments shows tremendous clinical potential, the NCI SBIR program issued TRT-focused contract solicitation for preclinical research in three consecutive years and awarded 16 contracts in this field. In addition, more than 30 TRT-related grants (14 of them funded by NCI SBIR program) have been awarded by different NCI funding mechanisms. Some of those projects are mature enough to enter the clinical testing phase within the next two years. To facilitate the translation of this investment in pre-clinical studies, there is a need for funding of first-in-human studies (Phase I/II clinical trials) to assess the feasibility, safety, and efficacy of novel TRT compounds (radiopharmaceuticals) or treatment strategies.

Project Goals

This contract solicitation seeks to stimulate research, development, and commercialization of innovative TRT techniques that could potentially improve the treatment efficacy and reduce toxicity to normal tissues. Proposals addressing clinical applications of the following technology areas are encouraged: clinical evaluation of innovative ligands and radiotracers for TRT; novel dosimetry techniques; new patient selection and treatment planning strategies taking into consideration the pharmacokinetics of the radiopharmaceutical and the resulting radiation dose delivered to the tumor and normal tissues in individual patients; and for mature projects, the combination of a TRT with conventional therapies.

To apply for this topic, offerors must have met IND requirements for their product or provide convincing data indicating that an IND will be accepted by the end of the Phase I period of performance.

The short-term goal of the project is to perform clinical studies testing the use of new TRT compounds or strategies for the treatment of cancer as described above.  The long-term goal of the project is to enable a small business to bring a fully developed TRT compound or novel TRT treatment strategy to the clinic and eventually to the market.

Phase I Activities and Deliverables

• For offerors who do not expect to have an IND accepted by September 2019, it is expected that specific plans for a pre-IND meeting with FDA will be described in the SBIR proposal. Pre-IND Phase I work may include:
  • Scale up and manufacturing of the new tested radiopharmaceutical

• • Completion of any activities required for IND submission
  • Finalized Clinical Trial Protocol for submission to FDA
• Examples of other Phase I activities include:
  • Clinical trial initiation activities such as protocol development, site selection and initiation
  • Development of methods and establishment of procedures for radiation dosimetry
  • Completion of regulatory approvals

IND acceptance is critical at the end of Phase I. Offerors that do not have IND acceptance and Phase I deliverables met will not be allowed to move to Phase II.

Phase II Activities and Deliverables

Clinical trials.  Depending on how advanced the development of a new therapeutic strategy is to be tested, the clinical trial might be: (i) feasibility, first-in-human, testing the biodistribution of the radiopharmaceuticals and assessment of therapeutic ratio based on radiation dosimetry; (ii) Phase 1, assessing the safety of the treatment and maximum tolerated dose of the tested compound; or (iii) Phase 2 assessing the optimal treatment strategy and its efficacy, preferably by comparing it in a randomized trial with that of the current standard of care.

• • • Implementation of appropriate dosimetry methods
    • Quantitative assessment of radiation doses delivered to tumor and normal tissues
    • Patient recruitment plan
    • Data safety management plan
    • Registration of clinical trial in ClinicalTrials.gov
    • Data collection
    • Completion of primary endpoint and secondary endpoint data analyses
    • Completion of final report of the primary outcome
    • Reporting of results in ClinicalTrials.gov