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DMPI: DelMar Presents Positive Data from VAL-083 Phase II Expansion Clinical Trial in Refractory Glioblastoma Multiforme

By Grant Zeng, CFA

OTC:DMPI

On November 23, 2015, DelMar Pharmaceuticals (DMPI) presented updated data from the fully enrolled 14-patient expansion cohort of the Company's ongoing Phase II clinical study of VAL-083 in refractory glioblastoma multiforme (GBM).

The expansion study is being conducted at Sarah Cannon Research Institute, Mayo Clinic, and UCSF Medical Center. The data were presented at the 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO) in San Antonio, Texas, held November 19-22. 

Background of the Phase I/II clinical trial 

DelMar initiated the Phase I/II clinical trial of VAL-083 for the treatment of refractory glioblastoma multiforme (GBM) or progressive secondary brain tumor in October 2011. The Phase I/II study is an open-label, single arm dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of VAL-083 in patients with histologically confirmed initial diagnosis of primary WHO Grade IV malignant glioma (GBM), now recurrent. Patients with prior low-grade glioma or anaplastic glioma are eligible if histologic assessment demonstrates transformation to GBM. Patients must have been previously treated for GBM with surgery, and/or radiation, if appropriate, and must have failed both Bevacizumab (Avastin) and temozolomide (Temodar), unless either or both are contra-indicated. Patients with brain tumors that have developed due to CNS metastases were eligible for the DelMar clinical trial at early doses. 

The primary outcome measures in the dose-modernization portion of the clinical trial will be the determination of maximum tolerated dose (MTD). Secondary outcome measures include tumor response in patients and pharmacokinetics. 

An initial phase of the Phase I/II study will involve dose escalation cohorts until a maximum tolerated dose (MTD) is established in the context of modern care. Once the modernized dosing regimen has been established, additional patients will be enrolled at the MTD in a registration directed Phase II clinical trial. 

The study was designed for patients to receive VAL-083 on days 1, 2, and 3 of a 21-day cycle. Tumor response is assessed according to RANO criteria prior to every other 21-day treatment cycle and patients exhibiting stable disease or tumor regression remained on VAL-083. Determination of MTD is based on 3+3 design.

Update on the Phase II Expansion Study 

In the Phase I dose-escalation portion of the study, VAL-083 was well tolerated at doses up to 40mg/m2 using a regimen of daily x 3 every 21 days. The 40 mg/m2/d dose exhibited a favorable safety profile, with a trend toward improved survival versus lower doses. Following determination of the maximum tolerated dose (MTD) at 40 mg/m2/d, a 14-patient Phase II expansion cohort was rapidly enrolled at a dose of 40 mg/m2/d on day 1, 2, 3 of a 21-day cycle. 

DelMar commenced enrollment in the 14-patient expansion cohort for the trial in GBM near the end of the second quarter of 2015. The purpose of the expansion cohort is to gain additional information about the safety and efficacy of VAL-083 at a 40mg/m2 dose prior to advancement into registration-directed Phase II/III clinical trials. 

On October 21, 2015, DelMar announced the full enrollment of the Phase II expansion cohort. 

To further explore the therapeutic window of VAL-083, DelMar also enrolled three (3) patients an interim dose of 45mg/m2. Patients enrolled in this clinical trial have failed both front-line therapy with temozolomide and second-line Avastin and, in most cases, one or more salvage therapies. 

Updated data were presented at the 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology being held November 19 - 22, 2015, in San Antonio, Texas. Here are the summary of the updated data: 

 
 - One subject previously treated with CCNU developed Grade 4 thrombocytopenia suggesting patients with prior nitrosourea treatment who may exhibit higher susceptibility to thrombocytopenia. The inclusion criteria were modified to account for this observation.

  • The 14th and final patient to be enrolled in the Phase II expansion cohort initiated treatment on October 14, 2015, and all patients enrolled in the Phase II expansion cohort have received at least one cycle of treatment to date. 
  • Safety observations in the Phase II expansion cohort to date are consistent with the Phase I dose-escalation cohort. Generally, observed myelosuppression is mild (Grade 1), with the exception of one patient. 
  • To date, 20 GBM patients failing standard front-line therapy and bevacizumab have been treated with an assumed well-tolerated therapeutic dose of VAL-083 (30mg/m2 /d & 40mg/m2 /d). A Kaplan Meyer survival estimate based on interim analysis of patients enrolled in the Phase II expansion cohort is consistent with observations made in the Phase I dose-escalation portion of the study. Preliminary analysis suggests a potentially meaningful survival benefit in this population following treatment with VAL-083 at doses ≥30 mg/m2 /d in comparison to published reports for the same population

    In 2009, Iwamoto reported a median overall survival of 2.0 months after failing bevacizumab for patients receiving only hospice care, and 5.2 months after failing bevacizumab for patients receiving further salvage therapy. The observed median survival to date following treatment with VAL-083 is 9.2 months

    Multiple historical NCI-sponsored clinical studies of VAL-083 demonstrated that, in general, tumor regression in brain cancer was achieved following therapy in greater than 40% of patients treated and stabilization was achieved in an additional 20% to 30%. In published clinical studies VAL-083 has previously been shown to have a statistically significant impact on median survival in high grade glioma brain tumors when combined with radiation versus radiation alone with results similar or superior to other chemotherapies approved for use in GBM.

    We think the interim survival data from the Phase II expansion cohort is highly promising. We are especially impressed with the safety profile of VAL-083 at the dose of 40 mg/m2/d and the projected greater than 9-month median survival. Taken together with historical and recently demonstrated clinical activity, these results suggest that VAL-083's distinct anti-cancer mechanism has the potential to overcome chemo-resistance and surpass the standard of care in the treatment of GBM. 

    A Registration Directed Phase II Trial and a Phase II/III to Begin in 2016 

    Based on the positive interim data, DelMar will request a meeting with the FDA in late 2015. The company plans to initiate a registration directed Phase II trial in refractory GBM in 1H2016. This could be a single arm or controlled trial after the feedback from the FDA. 

    Based on historical development of other products in GBM, it’s possible that DelMar may be able to obtain FDA approval to commercialize VAL-083 to treat patients who have failed other therapies from an Phase II registration-directed clinical trial, which will save significant costs of a large Phase III clinical trial. It’s also possible that the FDA may grant fast-track, accelerated approval and/or priority review status to VAL-083, which will enable DelMar to begin filing for commercial approval during the clinical trial process.  

    Based on historical precedent with the FDA, the Phase II registration directed trial are expected to mirror the Avastin approval study in that indication. Primary endpoints are overall survival and radiographic response. Secondary endpoints include quality of life, safety and tolerability. The trial will enroll approximately 100 patients. Patients with recurrent GBM who have failed or are ineligible for both Temodar® and Avastin® will be enrolled (the same population as in the current trial). 

    The recent failure of Avastin in the front line treatment of GBM has highlighted the need for new therapies in newly diagnosed patients, particularly those with unmethylated MGMT promoter regions who do not respond to standard of care with temozolomide.  

    Based on this unmet medical need, DelMar also plans to advance modernized dosing regimen into a Phase II/III trial in newly diagnosed patients with unmethylated MGMT promoter in parallel with the refractory GBM registration trial. The Company has begun designing this trial with KOLs.

    • Randomized groups:  Temodar vs. VAL-083;
    • Primary endpoints:  overall survival;
    • Secondary endpoints:  PFS6 & radiographic response;
    • N = 500 – 600 patients (with interim endpoint at ~10% enrollment); 


    The registration directed Phase II/III trial for the refractory GBM will take about 9 to 12 months. We estimate data from this will be available in 1H17 and an NDA will be filed in 2H17. The FDA approval will occur in 2018. 

    DelMar also plans to develop VAL-083 as the treatment of pediatric brain tumor.

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