Publications

PURPOSE

This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors.

PATIENTS AND METHODS

Part 1 (n=57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, maximum tolerated dose, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n=112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486.

RESULTS

At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug-drug interactions. The CC-486 RP2D was determined as 300 mg (once daily, days 1-14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days.

CONCLUSION

CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943).

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT). We characterized the incidence, risk factors, and long-term outcomes associated with TA-TMA by performing a comprehensive review of all adult patients (n = 1990) undergoing allogeneic HSCT at the Dana Farber Cancer Institute/Brigham and Women's Hospital between 2005 and 2013. Using the City of Hope criteria, we identified 258 patients (13%) with "definite" TMA and 508 patients (26%) with "probable" TMA. Mismatched donor transplantation (subdistribution hazard ratio [sHR], 1.79; 95% confidence interval [CI], 1.17 to 2.75; P = .007), sirolimus-containing graft-versus-host disease prophylaxis (sHR, 1.73; 95% CI, 1.29 to 2.34; P < .001), myeloablative conditioning (sHR, 1.93, 95% CI, 1.38 to 2.68; P < .001), and high baseline lactate dehydrogenase (LDH) level (sHR, 1.64; 95% CI, 1.26 to 2.13; P < .001) were associated with definite TMA. Moreover, positive cytomegalovirus serostatus (sHR, 1.41; 95% CI, 1.16 to 1.71; P < .001), high and very high disease risk index (sHR, 1.48; 95% CI, 1.12 to 1.96, P = .007), and high baseline LDH level (sHR, 1.25; 95% CI, 1.05 to 1.49; P = .011) were associated with probable TMA. In multivariable analyses, definite and probable TMA were each independently associated with higher mortality (HR, 5.24; 95% CI, 4.43 to 6.20 and HR, 2.12; 95% CI, 1.84 to 2.44, respectively), and long-term kidney dysfunction (HR, 5.43; 95% CI, 4.61 to 6.40 and HR, 2.20; 95% CI, 1.92 to 2.51, respectively). Definite and probable TMA were also independently associated with an increased risk of nonrelapse mortality and shorter progression-free survival. Our findings indicate that TA-TMA is common following HSCT and is independently associated with increased risk of death and kidney dysfunction.