CARE program: NCI and FDA interagency collaborations to support oncology small business entrepreneurs.

The National Cancer Institute's Small Business Innovation Research Development Center (NCI SBIR) supports the commercialization of novel cancer-related technologies by providing resources to 300-400 small businesses each year. Whereas Federal funding is crucial for the translation of technologies to the clinic, the majority of these technologies will need to undergo regulatory review to reach clinical testing. Many small businesses find navigating their regulatory pathway challenging, largely due to lack of regulatory expertise on small startup teams with limited revenue. In collaboration with the US Food and Drug Administration (FDA), NCI SBIR launched a new regulatory assistance program called Connecting Awardees with Regulatory Experts (CARE). The goal of the CARE program is to connect NCI-funded small businesses with the FDA to receive feedback on their regulatory questions during early-stage product development. The program has a multipronged support approach and also educates companies about the FDA process and existing resources. To date, 141 companies have participated in the interagency program. Follow-up surveys indicate that the program guided the companies in planning the next regulatory steps for their technology development (89%) and provided critical information that changed their future NCI small business grant project aims (81%). Overall, companies reported they would recommend the program to other companies (90%). This paper will discuss the CARE program outcomes as well as other NCI and FDA collaborations that support early-stage small businesses, including the joint development of funding opportunities and online resources that focus on the oncology startup community.

Correlation of Population Factors, Compliance with Masking and Social Distance, Vaccination, and COVID-19 Infection in Central Appalachia.

OBJECTIVES: Compliance with coronavirus disease 2019 (COVID-19) guidelines, including the use of masks and social distancing and vaccinations, has been poor. Our study examined what factors may identify those who will be more or less compliant, especially in regard to those with identified higher risk. METHODS: A telephone survey of 200 adult patients from two practices, one general internal medicine and the other rheumatology, was performed in May and June 2021. Questions included age, sex, perception of immunocompetence, smoking history, mask and social distancing compliance, COVID-19 symptoms and/or test-proven infection, and immunization status for COVID-19. Those agreeing to participate also underwent chart review for body mass index, physician-assessed immunocompetence, and diabetes mellitus. RESULTS: No clinical factors approached statistical significance for the prediction of compliance or noncompliance. Compliance with mask and social distancing highly correlated with vaccination and avoidance of infection, however. CONCLUSIONS: Attempts to improve compliance cannot be focused on any of the particular groups examined in this study.

An international, phase III randomized trial in patients with mucinous epithelial ovarian cancer (mEOC/GOG 0241) with long-term follow-up: and experience of conducting a clinical trial in a rare gynecological tumor.

OBJECTIVES: We evaluated four different treatment regimens for advanced-stage mucinous epithelial ovarian cancer. METHODS: We conducted a multicenter randomized factorial trial (UK and US). Patients were diagnosed with primary mEOC: FIGO stage II-IV or recurrence after stage I disease. Treatment arms were paclitaxel-carboplatin, oxaliplatin-capecitabine, paclitaxel-carboplatin-bevacizumab, or oxaliplatin-capecitabine-bevacizumab. Chemotherapy was given 3-weekly for 6 cycles, and bevacizumab (3-weekly) was continued as maintenance (for 12 cycles). Endpoints included overall-survival (OS), progression-free survival (PFS), toxicity and quality of life (QoL). RESULTS: The trial stopped after 50 patients were recruited due to slow accrual. Median follow-up was 59 months. OS hazard ratios (HR) for the two main comparisons were: 0.78 (p = 0.48) for Oxal-Cape vs. Pac-Carbo (each with/without bevacizumab), and 1.04 (p = 0.92) for bevacizumab vs. no bevacizumab. Corresponding PFS HRs were: 0.84 and 0.80. Retrospective central pathology review revealed only 45% (18/40) cases with available material had confirmed primary mEOC. Among these, OS HR for Oxal-Cape vs. Pac-Carbo was 0.36 (p = 0.14); PFS HR = 0.62 (p = 0.40). Grade 3-4 toxicity was seen in 61% Pac-Carbo, 61% Oxal-Cape, 54% Pac-Carbo-Bev, and 85% Oxal-Cape-Bev. QoL was similar between the four arms. CONCLUSION: mEOC/GOG0241 represents an example of a randomized rare tumor trial. Logistical challenges led to early termination, including difficulties in local histopathological diagnosis and accessing drugs outside their labelled indication. There was misalignment between central funders who support clinical trials in rare cancers and the deprioritisation of such work by those managing and funding research at a local level. Rare cancer trials should include centralised pathology review before treatment. Clinical trial registry number: ISRCTN83438782.

FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia.

On September 19, 2007, the U.S. Food and Drug Administration granted regular approval and expanded labeling for alemtuzumab (Campath); Genzyme Corporation, Cambridge, MA) as single-agent treatment for B-cell chronic lymphocytic leukemia (B-CLL). Alemtuzumab was initially approved in 2001 under accelerated approval regulations. Conversion to regular approval was based on a single study submitted to verify clinical benefit. Efficacy and safety were demonstrated in an open-label, international, multicenter, randomized trial of 297 patients with previously untreated, Rai stage I-IV B-CLL experiencing progression of their disease. Patients were randomized to either alemtuzumab, 30 mg i.v. over 2 hours three times per week on alternate days for a maximum of 12 weeks, or chlorambucil, 40 mg/m(2) orally every 28 days for a maximum of 12 months. The progression-free survival time, the primary study endpoint, was significantly longer in the alemtuzumab arm than in the chlorambucil arm. Both the overall and complete response rates were also significantly higher in the alemtuzumab arm. No differences in survival were observed. There were no new safety signals identified in patients receiving alemtuzumab. The most serious, and sometimes fatal, toxicities of alemtuzumab are cytopenias, infusion reactions, and infections.

Tumor expression of 4-1BB ligand sustains tumor lytic T cells.

Inadequate costimulation by solid tumors is generally believed to induce immune tolerance during primary tumor growth. We looked for tumor-specific immunity vs. tolerance in patients with Ewing's sarcoma. Circulating T cells from patients with progressively growing Ewing's tumors displayed MHC restricted tumor-induced proliferation and robust tumor lysis. Tumor-reactive T cells reside within the memory CD3+CD8+ subset and are CD28-/4-1BB+. Autologous Ewing's tumors expressed 4-1BBL, and tumor-induced T cell proliferation and activation required costimulation by 4-1BBL. Stimulation of PBL with anti-CD3/4-1BBL, but not anti-CD3/anti-CD28 induced tumor lytic effectors. Similarly, in a xenograft model, anti-CD3/4-1BBL expanded T cells controlled primary growth and prevented metastasis of autologous tumors while nonactivated and anti-CD3/anti-CD28 activated CD8+ cells did not. These results question prevailing models of tumor induced tolerance accompanying progressive tumor growth; rather, we show coexistence of progressive tumor growth and anti-tumor immunity, with costimulation provided by the tumor itself. They further demonstrate a potential new therapeutic role for 4-1BBL mediated costimulation in expanding tumor reactive CTLs for use in the adoptive immunotherapy of cancer.