Dmitri Pavlov

Antitumor Activity in Melanoma and Anti-Self Responses in a Phase I Trial With the Anti-Cytotoxic T Lymphocyte–Associated Antigen 4 Monoclonal Antibody CP-675,206

PURPOSE Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans. A phase I trial was conducted to test the safety of CP-675,206. PATIENTS AND METHODS Thirty-nine patients with solid malignancies (melanoma, n = 34; renal cell, n = 4; colon, n = 1) received an intravenous (IV) infusion of CP-675,206 at seven dose levels. The primary objective was to determine the maximum-tolerated dose and the recommended phase II dose. RESULTS Dose-limiting toxicities and autoimmune phenomena included diarrhea, dermatitis, vitiligo, panhypopituitarism and hyperthyroidism. Two patients experienced complete responses (maintained for 34+ and 25+ months), and there were two partial responses (26+ and 25+ months) among 29 patients with measurable melanoma. There have been no relapses thus far after objective response to therapy. Four other patients had stable disease at end of study evaluation (16, 7, 7, and 4 months). Additionally, five patients had extended periods without disease progression (36+, 35+, 26+, 24+, and 23+ months) after local treatment of progressive metastases. Longer systemic exposure to CP-675,206 achieved in higher dose cohorts predicted for a higher probability of response. CONCLUSION CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.

Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma

PURPOSE In phase I/II trials, the cytotoxic T lymphocyte-associated antigen-4-blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy. PATIENTS AND METHODS Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physicians choice of standard-of-care chemotherapy (temozolomide or dacarbazine). RESULTS In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor. CONCLUSION This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.

Phase I/II Trial of Tremelimumab in Patients With Metastatic Melanoma

PURPOSE Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with tremelimumab (CP-675,206), a fully human anti-CTLA4 monoclonal antibody, was tolerated and demonstrated antitumor activity in a single dose, dose-escalation phase I trial in patients with solid tumors. This phase I/II trial was conducted to examine safety of multiple doses of tremelimumab, to further assess efficacy, and to identify an appropriate dosing regimen for further development. PATIENTS AND METHODS Twenty-eight patients with metastatic melanoma received monthly intravenous infusions of tremelimumab at 3, 6, or 10 mg/kg for up to 1 year to determine recommended monthly phase II dose. During phase II, 89 patients received tremelimumab 10 mg/kg once every month or 15 mg/kg every 3 months. RESULTS No dose-limiting toxicity was observed in phase I once every month dosing. In phase II, 8 (10%) of 84 response-assessable patients attained objective antitumor responses; best overall objective response was one complete response and three partial responses in each dosing regimen. Most responses were durable (range, 3 to 30+ months). Most frequent treatment-related adverse events (AEs) were diarrhea, rash, and pruritus. Frequency of grade 3/4 AEs was 13% in the 15 mg/kg every 3 months arm and 27% in the 10 mg/kg once every month. Serious AEs were also less frequent in the 15 mg/kg once every 3 months cohort (9% v 23% in 10 mg/kg arm). CONCLUSION Multiple infusions of tremelimumab were generally tolerable and demonstrated single-agent antitumor activity. Both phase II regimens generated durable tumor responses. Based on its more favorable safety profile, 15 mg/kg every 3 months was selected for further clinical testing.

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial

BACKGROUND Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. METHODS In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. FINDINGS Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40-67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22-48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49-70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). INTERPRETATION The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease.

Comorbidity as a predictor of stage of illness for patients with breast cancer.

Objective:The purpose of this research was to determine whether comorbidity affects the stage at which breast cancer is diagnosed. Methods:Data from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (NCI) was merged with Medicare claims for 17,468 women diagnosed with breast cancer from 1993 to 1995. Results:Women with cardiovascular disease, musculoskeletal disorders, mild-to-moderate gastrointestinal disease, and nonmalignant benign breast disease had a 13%, 7%, 14%, and 24% lower odds, respectively, of being diagnosed with advanced breast cancer. Women with diabetes, other endocrine disorders, psychiatric disorders, or hematologic disorders increased the odds of a late-stage diagnosis by 19%, 11%, 20%, and 19% respectively. Mammography screening and contact with the medical care system decreased the odds of late-stage diagnosis. Discussion:Four hypotheses are suggested to explain this link between comorbid illness and stage at diagnosis: (1) the “surveillance” hypothesis, (2) the “physiological” hypothesis, (3) the “competing demand” hypothesis, and (4) the “death from other causes” hypothesis. Conclusions:Comorbidity may complicate the diagnostic decision-making process for breast cancer. The results suggest that contact with the medical care system improves the odds of early-stage diagnosis. Thus, barriers to access for people with chronic conditions may exacerbate those chronic conditions and increase the odds of late-stage breast cancer.

Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial.

Bosutinib is an oral, dual SRC/ABL1 tyrosine kinase inhibitor for resistant/intolerant chronic myeloid leukaemia (CML). We assessed the efficacy and safety of bosutinib 500 mg/d (n = 250) versus imatinib 400 mg/d (n = 252) after >24 months from accrual completion in newly diagnosed chronic phase (CP)‐CML (Bosutinib Efficacy and Safety in Newly Diagnosed CML trial [BELA]). Cumulative complete cytogenetic response (CCyR) rates by 24 months were similar (bosutinib, 79%; imatinib, 80%); cumulative major molecular response (MMR) rates were 59% for bosutinib and 49% for imatinib. Responses were durable; 151/197 vs. 172/204 and 125/153 vs. 117/131 responders remained on treatment and maintained CCyR and MMR, respectively. Since the 12‐month primary analysis, no new accelerated‐/blast‐phase transformations occurred with bosutinib; four occurred with imatinib. Early response (BCR‐ABL1/ABL1 ≤ 10%, 3 months) was associated with better CCyR and MMR rates by 12 and 24 months (both arms). Gastrointestinal events and liver function test elevations were more common, and neutropenia, musculoskeletal events and oedema were less common with bosutinib. Discontinuations due to adverse events were more common with bosutinib versus imatinib (most commonly alanine aminotransferase elevation: 4% vs. <1%); most occurred within the first 12 months. Cardiovascular adverse events were similar in both arms. Bosutinib continues to demonstrate good efficacy and manageable tolerability in newly diagnosed CP‐CML patients.

Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia

Bosutinib, an orally active, Src/Abl tyrosine kinase inhibitor, has demonstrated clinical activity and acceptable tolerability in chronic phase chronic myeloid leukemia (CP CML). This updated analysis of the BELA trial assessed the safety profile and management of toxicities of bosutinib versus imatinib in adults with newly diagnosed (≤6 months) CP CML after >30 months from accrual completion. Among patients randomized to bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252), 248 and 251, respectively, received ≥1 dose of study treatment. Adverse events (AEs; any grade) with bosutinib versus imatinib were significantly more common for certain gastrointestinal events (diarrhea, 70% vs. 26%; P < 0.001; vomiting, 33% vs. 16%; P < 0.001), alanine aminotransferase (33% vs. 9%; P < 0.001) and aspartate aminotransferase (28% vs. 10%; P < 0.001) elevations, and pyrexia (19% vs. 12%; P = 0.046). AEs significantly less common with bosutinib included edema (periorbital, 2% vs. 14%; P < 0.001; peripheral, 5% vs. 12%; P = 0.006), musculoskeletal (myalgia, 5% vs. 12%; P = 0.010; muscle cramps, 5% vs. 22%; P < 0.001; bone pain, 4% vs. 11%; P = 0.003), increased creatine phosphokinase (8% vs. 20%; P < 0.001), neutropenia (13% vs. 30%; P < 0.001), and leukopenia (9% vs. 22%; P < 0.001). Between‐group differences in the incidence of cardiac and vascular AEs were not significant. Diarrhea was typically transient, mostly Grade 1/2, occurring early during treatment, and was manageable with antidiarrheal medication. Despite higher rates of aminotransferase elevation with bosutinib, events were managed in most patients with dose modification and/or concomitant medication. Bosutinib had a manageable safety profile distinct from that of imatinib in patients with newly diagnosed CP CML. Am. J. Hematol. 89:947–953, 2014.

The development and validation of a comorbidity index for prostate cancer among Black men

BACKGROUND AND OBJECTIVES The purpose of this study was to develop a comorbidity index specific to Black Men with prostate cancer, because certain comorbidities and prostate cancer are particularly prevalent among this racial group. METHODS This research used the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database to develop an index of comorbidity burden based on survival, and the presence/absence of comorbid illness in 2,931 Black males diagnosed with prostate cancer. Comorbidity burden was recognized using inpatient, outpatient, and physician claims for a 2-year period prior to the diagnosis of prostate cancer. We compared five different statistical models, each with two-way, three-way, and/or four-way interactions among the comorbidities, and selected the model with only two-way interactions as the optimal choice. We demonstrated the utility of refining the simplest model, with 27 comorbidity categories only, by adjusting for the number of different diagnoses within statistically significant categories.

Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib

Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long‐term bosutinib treatment for Philadelphia chromosome‐positive (Ph+) leukemia based on treatment‐emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second‐/third‐/fourth‐line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first‐line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow‐up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib‐treated patients were 7%/10% overall with similar incidences observed with first‐line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure‐adjusted vascular/cardiac TEAE rates (patients with events/patient‐year) were low for second‐line or later bosutinib (0.037/0.050) and not significantly different between first‐line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first‐line and relapsed/refractory settings following long‐term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606–616, 2016.

Comorbidities and the Risk of Late-Stage Prostate Cancer

The degree to which comorbidities affect the diagnosis of prostate cancer is not clear. The purpose of this study was to determine how comorbidities affect the stage at which prostate cancer is diagnosed in elderly white and black men. We obtained data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute merged with Medicare claims data. For each patient, we estimated associations between stage of disease at diagnosis and each of the 27 comorbidities. The sample included 2,489 black and 2,587 white men with staged prostate cancer. Coronary artery disease, benign hypertension, and dyslipidemia reduced the odds of late-stage prostate cancer. A prior diagnosis of peripheral vascular disease, severe renal disease, or substance abuse increased the odds of being diagnosed with late-stage disease. The study shows some effect modification by race, particularly among white men with substance abuse, cardiac conduction disorders, and other neurologic conditions. The strongest predictors of late-stage prostate cancer diagnosis for both white and black men were age at diagnosis of at least 80 years and lack of PSA screening. Comorbidities do affect stage at diagnosis, although in different ways. Four hypotheses are discussed to explain these findings.