A combination of two molecularly targeted drugs, olaparib and the investigational agent AZD5363, was safe and yielded responses in patients with a variety of cancer types, including breast, ovarian, and prostate cancers, regardless of BRCA1/2 mutation status, according to data from the ComPAKT phase I clinical trial presented at the AACR Annual Meeting 2015, April 18-22.

“In this investigator-initiated clinical trial, we evaluated for the first time whether it is possible to safely combine the investigational AKT inhibitor AZD5363 with olaparib, a PARP [poly ADPribose polymerase] inhibitor recently approved by the FDA for treating advanced ovarian cancer associated with defective BRCA genes,” said Timothy Yap, MD, PhD, NIHR BRC clinician-scientist and consultant medical oncologist at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, United Kingdom.

“Here, we are reporting results from the dose-escalation portion of the trial, which showed that it was indeed possible to combine these drugs safely,” continued Yap.

“We also observed that several different cancer types responded to the combination, including cancers without BRCA1/2 mutations. These early results are very exciting because preclinical data had suggested that the olaparib and AZD5363 combination had the potential to be effective in a much wider population of patients than just those harbouring germline BRCA1/2 mutations.”

Yap also explained that the ComPAKT clinical trial is, to the best of his knowledge, the first phase I clinical trial using a combination of targeted agents to implement an intrapatient doseescalation design.

The design allowed individual patients to receive up to three predetermined escalating doses of AZD5363 in combination with a fixed dose of olaparib, but only if they were tolerating the drug combination well.

“This design allowed us to safely complete the doseescalation phase with at least six evaluable patients at each dose level, and in two schedules of the combination with just 20 patients in 7.5 months, which is unprecedented,” said Yap.

Of the 20 patients enrolled in the dose-escalation portion of the clinical trial, nine had germline BRCA1/2 mutations.

The patients had a variety of cancer types including advanced breast, ovarian, prostate, colorectal, cervical, pancreatic, uterine, and bladder cancers; mesothelioma; and gastrointestinal stromal tumours.

According to Yap, since the abstract was submitted, there are now four confirmed RECIST partial responses, including in a patient with BRCA1/2 wild-type ovarian cancer, two patients with BRCA1/2-mutant breast cancer, and a patient with BRCA1-mutant ovarian cancer.

Two patients had ongoing, prolonged RECIST disease stabilisation, including a patient with BRCA1/2 unknown breast cancer at six months and a patient with peritoneal mesothelioma at one year with tumour-marker reduction, who had previously responded before developing disease progression on treatment with a PI3K/mTOR inhibitor.

One patient with BRCA1/2-mutant advanced prostate cancer also continues to have a sustained response radiologically on MRI and by prostate-specific antigen Prostate Cancer Working Group 2 response criteria at 11 months.

Based on tolerability, the researchers established that the recommended phase II combination dose was 640 milligrammes of AZD5363 twice a day for two days each week, plus 300 milligrammes of olaparib twice a day.

The most commonly observed side effects were nausea, vomiting, fatigue, diarrhoea, and anaemia.

“We are currently assessing the drug combination at the recommended phase II combination dose in two different cohorts of patients within the doseexpansion phase of the trial,” said Yap.

Source: AACR