Analysis of Cancer Research Projects in Sub-Saharan Africa: A Quantitative Perspective on Unmet Needs and Opportunities.

PURPOSE: To evaluate the scope and types of cancer research projects in sub-Saharan Africa (SSA) to identify research gaps and inform future efforts. METHODS: This retrospective observational study summarized information on cancer research projects in SSA from the International Cancer Research Partnership (ICRP) between 2015 and 2020, alongside 2020 cancer incidence and mortality data from the Global Cancer Observatory. SSA cancer research projects were identified as led by investigators in SSA countries, or by investigators in non-SSA countries with collaborators in SSA, or in database keyword searches. Projects from the Coalition for Implementation Research in Global Oncology (CIRGO) were also summarized. RESULTS: A total of 1,846 projects were identified from the ICRP database, funded by 34 organizations in seven countries (only one, Cancer Association of South Africa, based in SSA); only 156 (8%) were led by SSA-based investigators. Most projects focused on virally induced cancers (57%). Across all cancer types, projects were most frequently related to cervical cancer (24%), Kaposi sarcoma (15%), breast cancer (10%), or non-Hodgkin lymphoma (10%). Gaps were observed for several cancers with higher incidence/mortality burden in SSA; for example, prostate cancer accounted for only 4% of projects but 8% of cancer-related deaths and 10% of new cases. Approximately 26% were dedicated to etiology. Treatment-related research declined over the study period (14%-7% of all projects), while projects related to prevention (15%-20%) and diagnosis/prognosis (15%-29%) increased. Fifteen CIRGO projects were identified; seven were relevant across multiple cancer types, and 12 focused either wholly or partially on cancer control (representing 50% of the total research effort). CONCLUSION: This analysis shows notable discrepancies between cancer burden and research projects and identifies opportunities for future strategic investments in cancer care in SSA.

Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial.

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.

Multisector Collaborations and Global Oncology: The Only Way Forward.

PURPOSE: At the 12th meeting of AORTIC (African Organization for Research and Training in Cancer) in Maputo, Mozambique, held between November 5 and November 8, 2019, a special workshop was organized to focus on the need for collaboration and coordination between governments and health systems in Africa with academic, industry, association, and other nongovernmental organizations to effect sustainable positive change for the care of patients with cancer. METHODS: Representatives from seven different projects in Africa presented implementation science and demonstration projects of their to date efforts in cancer system improvement including patient access, South-South partnerships, in-country specialized training, palliative care consortium, treatment outcomes, and focused pathology and diagnostic capacity building. Key partners of the various projects served as moderators and commentators during the session. RESULTS: From across all the presentations, lessons learned and exemplary evidence of the value of partnerships were gathered and summarized. CONCLUSION: The concluding synthesis of the presentations determined that with the broad needs across cancer requiring in-depth expertise at each point on a patient's journey, no single organization can effect change alone. Multipartner collaborations not only should be the norm but should also be coordinated so that efforts are not duplicated and maximum patient access to cancer diagnosis and care is achieved.

CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study.

BACKGROUND: Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. METHODS: This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing. FINDINGS: Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). INTERPRETATION: APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. FUNDING: Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.

Optimizing chemotherapy dose and schedule by Norton-Simon mathematical modeling.

BACKGROUND: to hasten and improve anticancer drug development, we created a novel approach to generating and analyzing preclinical dose-scheduling data so as to optimize benefit-to-toxicity ratios. METHODS: we applied mathematical methods based upon Norton-Simon growth kinetic modeling to tumor-volume data from breast cancer xenografts treated with capecitabine (Xeloda®, Roche) at the conventional schedule of 14 days of treatment followed by a 7-day rest (14-7). RESULTS: the model predicted that 7 days of treatment followed by a 7-day rest (7-7) would be superior. Subsequent preclinical studies demonstrated that this biweekly capecitabine schedule allowed for safe delivery of higher daily doses, improved tumor response, and prolonged animal survival. CONCLUSIONS: we demonstrated that the application of Norton-Simon modeling to the design and analysis of preclinical data predicts an improved capecitabine dosing schedule in xenograft models. This method warrants further investigation and application in clinical drug development.

Novel regimens of capecitabine alone and combined with irinotecan and bevacizumab in colorectal cancer xenografts.

BACKGROUND: Xenograft and mathematical models have shown that the antitumor activity of capecitabine can be increased by modifying the schedule from 14 days on, 7 off (14/7) to 7/7. MATERIALS AND METHODS: Capecitabine at two-thirds maximum tolerated dose (MTD) administered using 14/7 (267 mg/kg) and 7/7 (467 mg/kg) schedules, alone and in doublet and triplet combinations with irinotecan (40 mg/kg intraperitoneally) and bevacizumab (5 mg/kg intraperitoneally) were studied in mice bearing HT29 colorectal xenografts. RESULTS: Tumor growth inhibition was >100% in doublet and triplet regimens with capecitabine 7/7 compared with 70% and 98%, respectively, with 14/7. Increase in lifespan was significantly greater with the 7/7 triplet than the corresponding doublet without bevacizumab (288% versus 225%, respectively). CONCLUSION: Addition of bevacizumab to capecitabine and irinotecan significantly improved tumor growth inhibition and lifespan in the HT29 xenograft model. Modifying the capecitabine schedule from 14/7 to 7/7 improved the efficacy of doublet and triplet combinations without toxicity.

In vivo activity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models.

Modifying the capecitabine dosing schedule from 14 days on, 7 days off (14/7) to 7 days on, 7 days off (7/7) may enable higher doses and improved antitumor efficacy in colorectal cancer xenografts. Capecitabine 14/7 (267 or 400 mg/kg) and 7/7 (467 or 700 mg/kg) schedules in doublet and triplet combinations with optimally dosed bevacizumab (5 mg/kg) and oxaliplatin (6.7 mg/kg) were studied in female athymic nude mice bearing HT29 colorectal xenografts. Additional studies of suboptimally dosed bevacizumab (2.5 mg/kg) and capecitabine 7/7 (360 mg/kg) were done in a similar Colo205 tumor xenograft model. Monotherapy and combination regimens were administered to groups of 10 animals and compared with vehicle controls. In the HT29 model, tumor growth inhibition and increase in life span (ILS) were significantly greater with capecitabine 7/7 than with 14/7 (P<0.05). The additional benefit of capecitabine 7/7 versus 14/7 was biologically significant according to National Cancer Institute criteria (>25% ILS). Adding bevacizumab to capecitabine 7/7 resulted in significantly greater survival relative to either agent alone (P<0.0001). When oxaliplatin was added, efficacy was significantly better with the triplet combination including capecitabine 7/7 (tumor growth inhibition>100% and ILS 234%) compared with 14/7 (95% and 81%, respectively). In the Colo205 model, combination therapy with capecitabine 7/7 plus bevacizumab resulted in significantly greater survival relative to either agent alone (P<0.0001). In conclusion, in athymic nude mice bearing moderately thymidine phosphorylase-expressing HT29 or Colo205 colorectal xenografts, a capecitabine 7/7 schedule permits increased drug delivery compared with traditional 14/7 regimens, greatly improving monotherapy activity without major toxicity.

Phase I study of a novel capecitabine schedule based on the Norton-Simon mathematical model in patients with metastatic breast cancer.

PURPOSE: This study was conducted to determine, in patients with advanced-stage breast cancer, the maximum tolerated dose (MTD) of capecitabine administered orally for 7 days followed by a 7-day rest (7/7), a schedule based on a mathematical method for the optimization of anticancer drug scheduling. PATIENTS AND METHODS: Eligible patients had measurable, metastatic breast cancer. There was no limit to number of prior treatments. A standard, three-patients-per-cohort dose-escalation scheme used flat-dose capecitabine beginning at 1,500 mg orally twice daily (bid) on a 7/7 schedule. Each cohort was monitored for 28 days before escalation to the next cohort to assess for delayed toxicity. Response was evaluated radiographically every 12 weeks; toxicity was assessed every 2 weeks. RESULTS: Twenty-one patients were treated on study. The most frequently reported treatment-related grade 2/3 adverse events were hand-foot syndrome (29%), leukopenia/neutropenia (24%), and fatigue (19%). Grade 3 toxicity was transient and easily managed. Three patients experienced grade 3 hand-foot syndrome; one of these patients had grade 3 diarrhea. There were no grade 4 events. The MTD of capecitabine 7/7 is 2,000 mg twice daily. CONCLUSION: As predicted by mathematical modeling, capecitabine dosing for 7 days followed by a 7-day rest is well tolerated. Efficacy of this schedule is being determined in a phase II clinical trial in patients with advanced breast cancer.

Antitumor activity of capecitabine and bevacizumab combination in a human estrogen receptor-negative breast adenocarcinoma xenograft model.

BACKGROUND: Capecitabine and bevacizumab have each been shown to inhibit tumor growth. Their combination failed to improve survival in a phase III trial of metastatic breast cancer (MBC), although it should be noted patients had been heavily pretreated with anthracyclines and taxanes. Our aim was to evaluate whether combination treatment would increase tumor growth inhibition and survival in a breast cancer model. MATERIALS AND METHODS: Mice bearing KPL-4 human estrogen receptor-negative breast adenocarcinoma xenografts were given capecitabine orally daily for 14 days at the maximum tolerated dose (MTD) or half MTD, alone or with 5 mg/kg intraperitoneal bevacizumab twice weekly. RESULTS: Tumor growth inhibition (TGI) and increased life span (ILS) were superior in the combination groups versus monotherapy (p < 0.05). TGI and ILS were significantly improved in the high- versus low-dose capecitabine combination (p < 0.05). CONCLUSION: Capecitabine in combination with bevacizumab provides a basis for pursuing the combination for first-line treatment of MBC.