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327 Reformulation of Failed Chemotherapeutic Drugs

Fast-Track proposals will be accepted.

Number of anticipated awards: 2-4

Budget (total costs, per award):
Phase I: $225,000 for 9 months; Phase II: $1,500,000 for 2 years

It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

The deadline for receipt of all contract proposals submitted in response to this solicitation is: November 25, 2013 by 4:30 p.m. ET.

Summary:
Many promising chemotherapeutic candidates have failed to gain FDA approval due to adverse properties discovered in pre-clinical development or in human clinical trials. Such failures often occur due to unacceptable toxicity, although other limitations may also derail the development of promising anti-cancer agents. Novel drug delivery systems for cancer treatment that carry and deliver therapeutic payloads within close proximity of the tumor in vivo play a significant role in increasing the effectiveness of the treatment while decreasing the severity of toxicities. The successful delivery of well-established chemotherapeutics has been demonstrated previously using a number of platforms; however, such systems provide only incremental improvements in the overall therapeutic index of previously-approved drugs. An even greater opportunity is associated with reformulating once promising chemotherapeutic drugs that either failed to reach clinical trials or failed in clinical development. Among the limitations that reformulation strategies can address are poor oral bioavailability, poor solubility in biological fluids, inappropriate pharmacokinetics, and/or lack of efficacy within a tolerable dose range. To accelerate such efforts, the National Cancer Institute (NCI) requests proposals for the development of commercially-viable platforms for the reformulation of chemotherapeutic drugs that have failed previously in pre-clinical development or in human clinical trials.

Project Goals:
The goal of this project is to add new agents to the current arsenal of chemotherapeutic drugs by identifying and evaluating candidate delivery systems to enable the therapeutic potential of drugs that could not otherwise be delivered to humans in free form. The focus of this topic is on the reformulation of small-molecule chemotherapeutic agents. The proposed drug-delivery platform must yield a significant improvement in properties with respect to the free drug in order to enable the re-evaluation of the chemotherapeutic drug as a potential therapy for cancer treatment.

Proposals submitted under this topic must:
  • Name the small-molecule chemotherapeutic drug (i.e., the active pharmaceutical ingredient [API]) proposed for reformulation;
  • Describe to the greatest extent possible the mechanism by which the chemotherapeutic drug acts on cancer cells (i.e., mode of action);
  • Cite published literature and/or clinical data and/or other supporting evidence to clearly demonstrate that the chemotherapeutic drug is not deliverable in its free form;
  • Describe the drug-delivery platform/reformulation approach that will be used to reformulate the drug, and provide a compelling scientific rationale for why the solution may reduce or eliminate the adverse properties of the free drug.
The proposed drug-delivery platform/reformulation approach may utilize any technology capable of meeting the stated goals of this contract topic. Examples include the use of multi-functional targeted drug delivery platforms or multi-chamber chips carrying encapsulated drugs, although other approaches will be favorably considered. The final drug formulation may utilize an imaging agent(s) for a combination of therapeutic and diagnostic modalities, in order to provide real-time feedback and monitoring of therapy; however, such “theranostic” approaches are NOT required. Acceptable technologies/approaches under this contract may include, but are not necessarily limited to:
  • Devices involving novel tumor targeting and concentration schemes;
  • Novel drug loading and releasing schemes;
  • Novel drug delivery platforms, which are able to cross the blood-brain barrier, penetrate stromal barriers, overcome multi-drug resistance or treat metastatic cancer;
  • Novel therapeutic nanoparticle systems;
  • Antibody-drug conjugates;
  • Biomimetic constructs;
  • Virus-like particles (VLPs);
  • Combination therapies utilizing at least one chemotherapeutic agent meeting the above criteria.
Please note that the following approaches are NOT acceptable under this contract topic:
  • Chemical entities that have received FDA approval for any indication (cancer or otherwise) are NOT acceptable chemotherapeutic drug candidates under this topic.
  • Chemically-modified, failed chemotherapeutic agents are NOT acceptable drug candidates for this topic (i.e., traditional medicinal chemistry approaches are considered non-responsive).
Phase I Activities and Expected Deliverables:
  • Identification of appropriate cancer indication(s) for the proposed reformulated drug, and a detailed description of experimental strategy towards developing and delivering the construct containing the candidate chemotherapeutic agent;
  • Proof-of-concept attachment, encapsulation or incorporation of the candidate chemotherapeutic agent to the delivery vehicle;
  • In vitro stability of the drug-delivery construct, and drug release profile of the candidate chemotherapeutic agent from delivery vehicle (i.e., appropriately designed studies for the technology under development);
  • Proof-of-concept cell culture studies demonstrating efficacy in relevant tumor cell lines and lack of toxicity in relevant non-tumor cell lines;
  • Proof-of-concept small animal studies demonstrating therapeutic efficacy and improved therapeutic index, bioavailability, solubility, pharmacokinetics, and/or other relevant drug property as compared to the use of free drug, utilizing an appropriate animal model;
  • Plan and timeline for filing an IND with the FDA, including a strategy for scale-up of the reformulated chemotherapeutic drug construct.
Phase II Activities and Expected Deliverables (include at least three of the following):
  • Biodistribution studies in tumor-bearing animals (required);
  • Toxicology studies in small mammals (required);
  • Toxicology studies in second animal species (e.g., large mammals);
  • Pharmacokinetic/pharmacodynamics studies;
  • IND-enabling studies carried out in a suitable pre-clinical environment.

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