Clinical Path

A Phase I dose-escalation safety study of APR-246 monotherapy in patients with refractory hematological malignancies or prostate cancer was conducted to establish the safety, tolerability and highest feasible dose of APR-246. Subsequently, a Phase Ib/II dose-escalation study in p53-mutated platinum-sensitive and partially platinum-sensitive relapsed high-grade serous ovarian cancer (HGSOC) patients was initiated. All patients in the Phase Ib study received APR-246 in combination with carboplatin and pegylated liposomal doxorubicin (PLD). The Phase Ib component is complete and has established the safety, tolerability and pharmacokinetics for the combination. The Phase II component is currently enrolling patients

Ovarian Cancer

The lead target indication for APR-246 is ovarian cancer. As the 6th most common cancer in women, over 60,000 new cases are diagnosed worldwide each year. Many of these are late-stage (Stage III – IV) where the 5-year survival rates are below 40%. High-grade serous ovarian cancer accounts for 70-80% of all deaths from ovarian cancer. Over 90% of these patients are Stage III/IV and median survival is less than 4 years. Approximately 60% of ovarian cancer patients, and ≥95% of HGSOC patients, have p53 mutations at diagnosis. Therefore, combination treatment of APR-246 with chemotherapy could provide significant benefit.

The current standard of care for ovarian cancer and HGSOC is surgical resection of the tumor followed by combination chemotherapy with a platinum agent and a taxane. These chemotherapy regimens are effective in first-line ovarian cancer, but relapse and drug resistance are common.

APR-246 Combination Therapy in Ovarian Cancer

A Phase Ib study for relapsed platinum-sensitive and partially platinum-sensitive HGSOC has been completed, with data presented at the 2016 ASCO Annual Meeting and the 2016 ESMO Annual Meeting. Key safety results include:

  • APR-246 can be combined with the standard chemotherapy at relevant doses, allowing the highest of the tested doses to be selected as the dose for continuing the trial in a randomized Phase II clinical study.
  • APR-246 showed linear pharmacokinetics with no accumulation and low intra-patient variability. There was no indication of interaction between APR-246 and chemotherapy, supporting the combination of APR-246 with carboplatin and PLD at relevant doses.
  • The most frequent treatment-emergent adverse events have been low grade GI (nausea/vomiting), CNS (dizziness and fatigue) and hematological (neutropenia and thrombocytopenia) events. The hematological side effects can be attributed to the chemotherapy even if a contribution from the addition of APR-246 cannot be ruled out at this time.

To assess efficacy of APR-246 in combination with carboplatin and PLD, enrolled HGSOC patients were evaluated for response according to Response Evaluation Criteria In Solid Tumors (RECIST) guidelines.

  • Of 22 patients with radiologically measurable lesions, 3 had confirmed complete response, 10 had confirmed partial response, 8 had stable disease and 1 was not evaluable.
  • Of 2 patients with non-measurable disease, 1 had complete response and 1 had progressive disease.

In addition, the percentage change in lesion size from baseline was determined for evaluable patients and these results are shown graphically below. The red dotted line marks the 30% decrease in lesion size that is the RECIST threshold for partial response (PS = partially platinum sensitive-disease, S = platinum-sensitive disease).

The median progression-free survival for 22 evaluable patients, as measured by RECIST or GCIG, was 316 days (95% CI, 280-414 days) and was not influenced by the length of previous platinum treatment-free interval or dose cohort. These results in recurrent HGSOC patients are highly encouraging and support continued development in Phase II.

APR-246 in Combination Therapy for Other Cancer Indications

In addition to the ongoing Phase II clinical trial in platinum-sensitive and partially platinum-sensitive HGSOC, we plan to initiate Phase Ib clinical studies for 3 new indications in 2017.

  • Platinum-resistant HGSOC
  • Esophageal cancer
  • Myelodysplastic syndrome

In light of the high prevalence of p53 mutations in many tumor types, we are actively conducting preclinical research to expand the number of potential indications in which APR-246 may offer therapeutic benefit.