Challenges of HIV Lymphoma Clinical Trials in Africa: Lessons From the AIDS Malignancy Consortium 068 Study.

The purpose of this article is to describe lessons from the first lymphoma clinical trial conducted by the AIDS Malignancy Consortium (AMC) in sub-Saharan Africa (SSA). AMC-068 was a randomized phase II comparison of intravenous versus oral chemotherapy for HIV-positive diffuse large B-cell lymphoma. Opening in 2016, AMC-068 planned to enroll 90 patients (45 per arm) in Kenya, Malawi, Uganda, and Zimbabwe over 24 months and follow patients for 24 months to assess overall survival. In 2018, the study closed after screening 42 patients but enrolling only 7. Challenges occurred during protocol development, pre-activation, and postactivation. During protocol development (2011-2012), major obstacles were limited baseline data to inform study design; lack of consensus among investigators and approving bodies regarding appropriateness of the oral regimen and need for randomized comparison with cyclophosphamide, doxorubicin, vincristine, and prednisone; and heterogeneity across sites in local standards for diagnosis, staging, and treatment. During pre-activation (2012-2016), challenges included unexpected length and layers of regulatory approval across multiple countries, need to upgrade pathology capacity at sites, need to augment existing chemotherapy infusion capacity at sites, and procurement issues for drugs and supplies. Finally, during postactivation (2016-2018), challenges included long delays between symptom onset and screening entry for many patients, leading to compromised performance status and organ function; other patient characteristics that frequently led to exclusion, including high tumor proliferative index or other pathologic features that were disallowed; and costs of routine diagnostic procedures often being borne by patients, which also contributed to pre-enrollment delays. Lessons from AMC-068 are being applied to the design and conduct of new AMC lymphoma trials in SSA, and the study has contributed to a strong operational foundation that will support innovative clinical trials in the future.

Clinical Trials for Treatment and Prevention of HIV-Associated Malignancies in Sub-Saharan Africa: Building Capacity and Overcoming Barriers.

PURPOSE: The aim of this study was to review the current status of clinical trials for HIV-associated malignancies in people living with HIV in sub-Saharan Africa (SSA) and efforts made by the AIDS Malignancy Consortium (AMC) to build capacity in SSA for HIV malignancy research. METHODS: All malignancy-related clinical trials in 49 SSA countries on ClinicalTrials.gov were reviewed and evaluated for inclusion and exclusion criteria pertaining to HIV status. Additional studies by AMC in SSA were compiled from Web-based resources, and narrative summaries were prepared to highlight AMC capacity building and training initiatives. RESULTS: Of 96 cancer trials identified in SSA, only 11 focused specifically on people living with HIV, including studies in Kaposi sarcoma, cervical dysplasia and cancer, non-Hodgkin lymphoma, and ocular surface squamous neoplasia. Recognizing the increasing cancer burden in the region, AMC expanded its clinical trial activities to SSA in 2010, with 4 trials completed to date and 6 others in progress or development, and has made ongoing investments in developing research infrastructure in the region. CONCLUSION: As the HIV-associated malignancy burden in SSA evolves, research into this domain has been limited. AMC, the only global HIV malignancy-focused research consortium, not only conducts vital HIV-associated malignancies research in SSA, but also develops pathology, personnel, and community-based infrastructure to meet these challenges in SSA. Nonetheless, there is an ongoing need to build on these efforts to improve HIV-associated malignancies outcomes in SSA.

An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer.

PURPOSE: Endoglin, an endothelial cell membrane receptor expressed on angiogenic tumor vessels, is essential for angiogenesis and upregulated in the setting of VEGF inhibition. TRC105 is an anti-endoglin IgG1 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with bevacizumab. EXPERIMENTAL DESIGN: Patients (n = 38) with advanced solid tumors, Eastern Cooperative Group performance status 0-1, and normal organ function were treated with escalating doses of TRC105 plus bevacizumab until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. RESULTS: TRC105 and bevacizumab were well tolerated at their recommended single-agent doses (10 mg/kg) when the initial dose of TRC105 was delayed by one week and divided over 2 days to limit the frequency of headache. The concurrent administration of bevacizumab and TRC105 did not otherwise potentiate known toxicities of TRC105 or bevacizumab. Hypertension and proteinuria were observed, though not at rates expected for single-agent bevacizumab. Several patients who had previously progressed on bevacizumab or VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) treatment experienced reductions in tumor volume, including two partial responses by RECIST, and 6 remained without progression for longer periods than during their prior VEGF inhibitor therapy. CONCLUSIONS: TRC105 was well tolerated with bevacizumab and clinical activity was observed in a VEGF inhibitor-refractory population. Ongoing clinical trials are testing TRC105 in combination with bevacizumab in glioblastoma and with VEGFR TKIs in renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcoma.

Modelling the sitagliptin effect on dipeptidyl peptidase-4 activity in adults with haematological malignancies after umbilical cord blood haematopoietic cell transplantation.

BACKGROUND AND OBJECTIVES: Dipeptidyl peptidase-4 (DPP4) inhibition is a potential strategy to increase the engraftment rate of haematopoietic stem/progenitor cells. A recent clinical trial using sitagliptin, a DPP4 inhibitor approved for type 2 diabetes mellitus, has been shown to be a promising approach in adults with haematological malignancies after umbilical cord blood (UCB) haematopoietic cell transplantation (HCT). On the basis of data from this clinical trial, a semi-mechanistic model was developed to simultaneously describe DPP4 activity after multiple doses of sitagliptin in subjects with haematological malignancies after a single-unit UCB HCT. METHODS: The clinical study included 24 patients who received myeloablative conditioning followed by oral sitagliptin with single-unit UCB HCT. Using a nonlinear mixed-effects approach, a semi-mechanistic pharmacokinetic-pharmacodynamic model was developed to describe DPP4 activity from these trial data, using NONMEM version 7.2 software. The model was used to drive Monte Carlo simulations to probe the various dosage schedules and the attendant DPP4 response. RESULTS: The disposition of sitagliptin in plasma was best described by a two-compartment model. The relationship between sitagliptin concentrations and DPP4 activity was best described by an indirect response model with a negative feedback loop. Simulations showed that twice daily or three times daily dosage schedules were superior to a once daily schedule for maximal DPP4 inhibition at the lowest sitagliptin exposure. CONCLUSION: This study provides the first pharmacokinetic-pharmacodynamic model of sitagliptin in the context of HCT, and provides a valuable tool for exploration of optimal dosing regimens, which are critical for improving the time to engraftment in patients after UCB HCT.

Prevalence and correlates of pain and pain treatment in a western Kenya referral hospital.

BACKGROUND: Pain is often inadequately evaluated and treated in sub-Saharan Africa (SSA). OBJECTIVE: We sought to assess pain levels and pain treatment in 400 hospitalized patients at a national referral hospital in western Kenya, and to identify factors associated with pain and pain treatment. DESIGN: Using face-validated Kiswahili versions of two single-item pain assessment tools, the Numerical Rating Scale (NRS) and the Faces Pain Scale-Revised (FPS-R), we determined patients' pain levels. Additional data collected included patient demographics, prescribed analgesics, and administered analgesics. We calculated mean pain ratings and pain management index (PMI) scores. RESULTS: Averaged between the NRS and FPS-R, 80.5% of patients endorsed a nonzero level of pain and 30% of patients reported moderate to severe pain. Older patients, patients with HIV, and cancer patients had higher pain ratings. Sixty-six percent of patients had been prescribed analgesics at some point during their hospitalization, the majority of which were nonopioids. A majority of patients (66%) had undertreated pain (negative scores on the PMI). CONCLUSION: This study shows that hospitalized patients in Kenya are experiencing pain and that this pain is often undertreated.