Following a recent independent Data and Safety Monitoring Board (DSMB) recommendation and subsequent futility analysis, Cambridge, Massachusetts-based Merrimack Pharmaceuticals, has decided to stop the Phase II HERMIONE study of MM-302 (HER2 antibody-targeted liposomal doxorubicin) in HER2-positive metastatic breast cancer patients who had previously been treated with trastuzumab (Herceptin®), pertuzumab (Perjeta®) and ado-trastuzumab emtansine (T-DM1, Kadcyla®).

Merrimack expects to provide further details about MM-302, as well as the results of its full pipeline review, in January 2017.

Clinical Trial
MM-302 is an antibody-drug conjugate. The drug is composed of a HER2-targeted antibody linked to the cytotoxic chemotherapy liposomal doxorubicin.

The phase II HERMIONE clinical trial (NCT02213744) was designed to evaluate MM-302 at 30 mg/m2 every 3 weeks) plus trastuzumab versus physician’s choice of chemotherapy plus trastuzumab as a treatment for patients with anthracycline-naïve, HER2-positive locally advanced or metastatic breast cancer following previous treatment with trastuzumab, pertuzumab, and T-DM1. Chemotherapy options included gemcitabine, capecitabine and vinorelbine. [1]

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No benefit over comparator
The decision to stop the trial was made following the DSMB’s opinion that continuing would be unlikely to demonstrate benefit over the comparator treatments. Subsequent to this recommendation, a futility assessment was performed that confirmed the DSMB’s opinion. Both the treatment and control arms were found to have shorter than expected median progression free survival.

No safety concerns
Importantly, there were no new or unexpected safety concerns. Patients currently enrolled in the trial may choose to continue on their assigned treatment based upon discussion with their study physician.

“Late line HER2-positive breast cancer is very difficult to treat, especially in this new and previously unstudied group of patients who appear to experience rapid cancer progression following treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine,” noted Istvan Molnar, MD, Vice President of Clinical Development at Merrimack Pharmaceuticals.

“While we are disappointed with this outcome, we would like to thank the study Steering Committee, the investigators and, most importantly, the patients who participated in the HERMIONE trial. We will report our learnings from this study at a later date,” Molnar added.

Phase I data at AACR 2015
Phase I data presented during the 2015 annual meeting of the American Association of Clinical Research suggested promising signs of clinical activity when MM-302 was given to heavily pretreated patients with metastatic, HER2-positive, breast cancer. This study enrolled 69 patients who had received at least 4 prior systemic therapies.

The researchers concluded that, at the time of the presentation of the phase I trial data, MM-302 had a manageable safety profile as a monotherapy, in combination with trastuzumab and with trastuzumab and cyclophosphamide. Based on these results, MM-302 was evaluated at a dose of 30 mg/m2 Q3W in combination with trastuzumab in the randomized phase II HERMIONE trial in anthracycline naïve HER2-positive locally advanced/mBC patients previously treated with trastuzumab, pertuzumab and T-DM1.

Note: In the phase I trial, patients were randomized to be treated with either:

  • MM-302 alone (8, 16, 30, 40 and 50 mg/m2, Q4W) (Arm 1) or
  • MM-302 (30 and 40 mg/m2, Q4W) + trastuzumab (4 mg/kg, Q2W) (Arm 2), or
  • MM-302 (30 mg/m2, Q3W) + trastuzumab (6 mg/kg, Q3W) (Arm 3), or
  • MM-302 (30 mg/m2, Q3W) + trastuzumab (6 mg/kg, Q3W) + yclophosphamide (450 mg/m2, Q3W) (Arm 4).

Furthermore, patients treated with arms 3 and 4 regimens received a single 3-7 mg/m2 (approximately 10.8 mCi) dose of 64Cu-MM-302 followed by PET/CT to assess for MM-302 tumor deposition.

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