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Bevacizumab

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Dianhydrogalactitol

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VAL-083 given by intravenous infusion with a starting dose of 1.5 mg/m2 IV. Escalating doses to be administered in sequential dose cohorts.

VAL-083 (Dianhydrogalactitol)

Howard A Burris, M.D.

Manish Patel, M.D.

Nicholas Butowski, M.D.

Sani Kizilbash, M.D.

Gerald Falchook, M.D.

The purpose of this Phase 1/2, open-label, single-arm study is to determine the safety and the maximal tolerated dose (MTD) of VAL-083 in patients with recurrent malignant glioma. Pharmacokinetic (PK) properties will be explored and tumor responses to treatment will be evaluated.

Recurrent glial tumors of the brain continue to be one of the most challenging malignancies to treat. Median survival for patients with recurrent disease is approximately 6 months for glioblastoma multiforme. Bevacizumab is used for treatment of recurrent disease; however patients who fail bevacizumab do not have many treatment options.

Metastases to the brain are the most common intracranial tumors in adults and occur ten times more frequently than primary brain tumors. It is estimated that 8 - 10% of cancer patients may develop symptomatic metastatic tumors in the brain. Systemic therapy is rarely used for primary treatment of brain metastases because many tumors that metastasize to the brain are not chemosensitive or have been already heavily pretreated with potentially effective agents, and poor penetration through the blood brain barrier is an additional concern.

Dianhydrogalactitol (DAG) rapidly penetrates both the cerebrospinal fluid (CSF) and the blood-brain barrier and accumulates in brain tissue. Clinical study of DAG in patients with GBM or with progressive secondary brain tumors is warranted. Patients with secondary brain metastases were allowed to enroll into the current protocol in Cohorts 2 and 3; however, enrollment ceased with Amendment 5 and will not be continued beyond Cohort 3.

This study will utilize a standard 3 + 3 dose escalation design, until the MTD or the maximum specified dose has been reached. In Phase 2, additional patients with GBM will be treated at the MTD (or other selected optimum Phase 2 dose) to measure tumor responses to treatment.

Safety Study of VAL-083 in Patients With Recurrent Malignant Glioma

Open-label, Single Arm, Safety and Tolerability Dose Escalation Study of VAL-083 in Patients With Recurrent Malignant Glioma

The Clinical Study Report for this trial will be prepared and provided to U.S. F.D.A. as required by applicable regulatory requirement(s). Each participating trial investigator has been provided a copy their patient data captured in the electronic data base for this trial.

The determination of MTD will be based on analysis of tolerance data from the first cycle of therapy in each dose group.

Tumor assessment every other treatment cycle, as long as patient continues to demonstrate response or stable disease and tolerates therapy.

Plasma will be analyzed to estimate appropriate PK parameters (Cmax, Tmax, AUC, elimination half-life, drug clearance, mean residence time, and volume of distribution).

DelMar Pharmaceuticals, Inc.

Newly diagnosed GBM patients who have completed chemoradiation treatment with temozolomide and received no subsequent maintenance temozolomide

The dosing regimen for patients will be VAL-083 (30 mg/m2) administered IV for 3 consecutive days at the beginning of every 21-day cycle. Patients will continue to receive VAL 083, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation.

VAL-083, Dianhydrogalactitol

Barbara O'Brien, M.D.

The purpose of this phase 2, two arm, biomarker-driven study is to determine if treatment of O-6-methylguanine-DNA methyltransferase (MGMT) unmethylated glioblastoma with VAL-083 improves overall survival (OS), compared to historical control, in the adjuvant or recurrent setting.

Recurrent GBM is characterized by a dismal prognosis, with a median overall survival of 6.9 months. While a standard of care is established for the initial treatment of GBM - radiation with concurrent and adjuvant temozolomide chemotherapy - management of recurrent disease (NCCN, 2014) remains suboptimal. Treatment options include repeat surgery, re-irradiation, or chemotherapy (including experimental targeted therapies, biologic agents, and immunotherapies). Only a minority of patients has response to these treatments, and the resultant benefits in progression-free and overall survival are in the order of weeks to months.

Prognosis and response to therapy are known to be better in patients with a methylated MGMT promoter gene. Epigenetic silencing of MGMT by promoter methylation is an important factor in predicting outcome for patients with GBM treated with temozolomide. Approximately 66% of GBM tumors are MGMT unmethylated (high expression of MGMT), which through a MGMT repair mechanism, confers resistance to temozolomide, the standard chemotherapy treatment of GBM.

VAL-083, Dianhydrogalactitol (DAG), unlike temozolomide, is demonstrated to be active independent of MGMT resistance mechanisms, in vitro. Thus, it may provide a treatment option for those patients that are considered likely to be poor responders to temozolomide.

This is a non-comparative, two arm, biomarker-driven study with VAL-083 in GBM patients with either recurrent disease (Group 1) or newly diagnosed GBM patients requiring maintenance therapy after chemoradiation with temozolomide (Group 2).

Group 1: A total of up to 83 patients with recurrent/progressive GBM will be enrolled. This will include 35 patients treated at 40 mg/m2 and up to 48 patients treated at 30 mg/m2.

Group 2: Up to an additional 36 newly diagnosed GBM patients who have completed chemoradiation treatment with temozolomide and received no subsequent maintenance temozolomide will be enrolled.

Eligible patients will receive VAL-083 IV on days 1, 2, and 3, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation (disease progression, death, intolerable toxicities, investigator's judgment, or withdrawal of consent). Disease status will be evaluated with clinical and MRI evaluation every other 21-day cycle, while the patient is receiving VAL-083 treatment, and then approximately every 42 ± 7 days while remaining on study. Symptom burden will be evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) completed by patients at baseline and at the time of each imaging evaluation.

Interval medical histories, targeted physical exams, neurologic evaluations, complete blood counts, and other laboratory and safety assessments will be performed approximately every 21-days. Blood samples will be taken at Cycle 1 Day 1 pre-dose, 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of iv infusion with VAL-083 to determine the PK profile and dose-exposure relationship of VAL-083.

Toxicity will be evaluated and documented using the NCI CTCAE version 4.

This study will take approximately 36 months to enroll.

Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Glioblastoma in the Adjuvant or Recurrent Setting

Phase 2 Study of VAL-083 Treatment for MGMT Unmethylated Bevacizumab-naïve Glioblastoma in the Adjuvant or Recurrent Setting

The Clinical Study Report for this trial will be prepared and provided to U.S. F.D.A. as required by applicable regulatory requirement(s). Each participating trial investigator will be provided a copy their patient data captured in the electronic data base for this trial.

Length of time from start of treatment (Day 1) until patient death

Time from start of treatment (Day 1) until to the first occurrence of progression or patient death, whichever occurs first

The median length of time from start of treatment (Day 1) until to the first occurrence of progression or patient death, whichever occurs first

The median length of time from start of treatment (Day 1) until patient death

Overall number of tumor complete response (CR) or partial response (PR) determined via MRI assessment

Length of time tumor continues to demonstrate either complete response (CR) or partial response (PR) via MRI assessment

To confirm safety and tolerability of VAL-083 using NCI CTCAE v.4 to assess adverse events

MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT)

PK profile and dose-exposure relationship of VAL-083

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Safety Study of VAL-083 in Patients With Recurrent Malignant Glioma	NCT01478178	Glioma Glioblastoma Glioblastoma Mu... GBM Brain Cancer	VAL-083 (Dianhy...	18 Years -	Kintara Therapeutics, Inc.
Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Glioblastoma in the Adjuvant or Recurrent Setting	NCT02717962	Glioma Glioblastoma Glioblastoma Mu... GBM Brain Cancer	VAL-083, Dianhy...	18 Years -	Kintara Therapeutics, Inc.

Spots Global Cancer Trial Database for temozolomide failure