Novel Agent Reveals Its Promise in Combinations for Advanced Cancers

Timothy A. Yap, MBBS, PhD, MRCP, BSc

Preliminary results from an ongoing phase I study have revealed the potential of a novel small-molecule inhibitor in 3 combinations for patients with advanced cancers. AZD6738 is being investigated in parallel combinations with carboplatin, olaparib (Lynparza), or durvalumab (MEDI4736), with responses noted with each combination as of the interim analysis. Preliminary data from the study (NCT02264678) were presented during the 2016 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

“[AZD6738] can be combined feasibly with single-agent recommended phase II doses of olaparib, durvalumab, and carboplatin given at AUC 5 in a 3-week schedule,” said Timothy A. Yap, MBBS, PhD, MRCP, BSc, when presenting the findings.

AZD6738 is an oral ataxia telangiectasia Rad3-related (ATR) inhibitor that is highly selective for ATR and the closely related kinases, ATM and DNAPK, noted Yap, a clinical scientist at The Institute of Cancer Research, and a consultant medical oncologist at The Royal Marsden. In preclinical studies with xenograft models of various cancers, AZD6738 showed efficacy as both a monotherapy and in combination with either olaparib or carboplatin. “These robust preclinical data provided the strong rationale for us to proceed to a phase I clinical trial,” Yap said. Preclinical data suggest that the ATR inhibitor would sensitize to DNA-damaging therapies and prevent DNA damage repair.

The phase I trial includes 3 modules investigating different combinations at the same time. Module 1 explored AZD6738 combined with carboplatin; module 2, a combination with olaparib; and module 3, a combination with durvalumab.

As of the interim analysis, 37 patients had been enrolled in module 1, including 9 patients with colorectal cancer, 6 with ovarian cancer, 6 with mesothelioma, 3 with non—small cell lung cancer (NSCLC), and 13 patients with other cancers. The average age of the patients was 60, and just over half were female. All patients had an ECOG performance status of 0 or 1.

AZD6738 was investigated at various doses across 7 cohorts to determine the best tolerated dose. The first cohort (n = 4) was given AZD6738 at a dose of 20 mg twice daily for days 4 through 20 of a 21-day cycle, as well as AUC 5 of carboplatin on day 1, but this dose was not well tolerated. Patients experienced neutropenia and thrombocytopenia, which caused treatment delays. Ultimately, the investigators reached a dose of 40 mg once daily on days 1 and 2, which was established as the phase II recommended dose.

Across all cohorts in module 1, the most common grade ≥3 ad- verse events (AEs) experienced were anemia (18.9%), neutropenia (18.9%), thrombocytopenia (18.8%), and hypophosphatemia (5.4%). There were 3 confirmed partial responses (PRs), 1 each in a patient with cervical cancer, rectal adenocarcinoma with ATM loss, and a patient with ATM-mutant clear cell ovarian cancer.

In the second module, 36 patients were enrolled, including 7 with hormone receptor—positive breast cancer, 6 with ovarian cancer, 4 with triple-negative breast cancer (TNBC), and 19 with other cancers. The average age was 54.3 years, more than half of the patients were female, and 57.1% of the patients had an ECOG performance status of 1.

The module included 8 cohorts, 3 of which are ongoing, of various doses of AZD6738 combined with olaparib twice daily in a 28-day cycle. The first cohort tested AZD6738 at 60 mg once daily on days 1 to 5 and 15 to 19, and the dosage was increased from there. Dose-limiting toxicities were reached in 1 cohort at 160 mg once daily of AZD6738 on days 1 to 14 and 200 mg of olaparib twice daily, with patients experiencing neutropenia and thrombocytopenia.

Frequent AEs of grade ≥3 severity across all cohorts included neutropenia, low white cell count, anemia, thrombocytopenia, and ascites. There were 3 confirmed PRs: 2 in patients with BRCA1-mutated TNBC and 1 in a patient with BRCA2-mutated estrogen receptor—positive breast cancer.

One patient with BRCA1-mutated TNBC in the second module experienced a 70% PR, by RECIST criteria, on the first scan and re- mains on the trial at 9 months. The patient received AZD6738 at a dose of 80 mg on days 1 to 7 of a 28-day cycle and 200 mg of olaparib twice daily. Yap noted that the patient is on her way to achieving a complete response.

Twelve patients have been enrolled in module 3, including 6 with NSCLC and 6 with head and neck squamous cell carcinoma (HNSCC) across 3 cohorts, 1 of which is ongoing. The average age was about 58 years, 91.7% of the patients were male, and two-thirds had an ECOG performance status of 1.

AZD6738 was administered at 80 mg twice daily as a 14-day run-in and then on days 22 through 28 of the 28-day cycle with 1500 mg of durvalumab. Subsequent cohorts increased the dose of AZD6738 to 160 mg. No dose-limiting toxicities were noted in any of the cohorts.

Grade ≥3 AEs included lower respiratory tract infection, lung infection, hyponatremia, obstructive airways disorder, pneumo- nia aspiration, and lymphopenia, experienced by 1 patient each. “These were mainly infections that were disease-related rather than drug-related. Overall, this combination is well tolerated. We did observe immune-related toxicities, but these were mild and were mainly grade 1 to 2,” Yap said.

One complete response was noted in a patient with NSCLC, and a PR was experienced by a patient with HNSCC.

Overall, AZD6738 showed early signs of ef cacy with each of the combinations. “All 3 combinations were associated with early signals of antitumor activity, but of course, these are preliminary results and we will need further data before we can actually estab- lish if these are truly active and synergistic combinations,” Yap said. “AZD6738 is dose-proportional, has a half-life of approxi- mately 11 hours, and, importantly, there are no observed drug—drug interactions with any of the combination partners to date.”

Although a number of responses were seen in patients with an ATM deficiency or mutation, patients were not enrolled based on their ATM status. An expansion cohort exploring patients with ATM-deficient gastric cancer was added to module 2, which had already enrolled 6 patients at the time of the conference.

Reference:

Yap TA, Krebs MG, Postel-Vinay S, et al. Phase I modular study of AZD6738, a novel oral, potent and selective ataxia telangiectasia Rad3- related (ATR) inhibitor in combination with carboplatin, olaparib or dur- valumab in patients with advanced cancers. Presented at: 28th EORTC- NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 29-December 2, 2016; Munich, Germany. Abstract 1LBA.