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Bevacizumab

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Alkylating Agents

Up to 120 eligible patients will be randomized to receive VAL-083.

Up to 60 patients will be randomized to receive "Investigator's choice of salvage therapy" temozolomide, lomustine, or carboplatin

VAL-083 given by intravenous infusion at a dose 40 mg/m2 IV on days 1, 2, and 3 of a 21-day treatment-cycle, for up to 12, 21-day treatment cycles

VAL-083, Dianhydrogalactitol

The product label for temozolomide (Temodar®) provides the following dosing information.

Newly Diagnosed GBM: 75 mg/m2 for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days 1-5 of a 28-day cycle of Temodar® for 6 cycles.

Refractory Anaplastic Astrocytoma: Initial dose 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle.

Physician's Choice of Salvage Therapy - temozolomide

The product label for lomustine (CeeNu; lomustine; CCNU) provides the following dosing information.

The recommended dose of lomustine in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m2 as a single oral dose every 6 weeks In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks.

Physician's Choice of Salvage Therapy - lomustine

The product label for (Paraplatin) carboplatin Injection provides the following dosing information.

As a single agent at a dosage of 360mg/m2 IV on day 1 every 28 days Alternatively, the carboplatin dose may be calculated by the Calvert formula below Calvert formula for carboplatin dosing: Total Dose (mg) = (target AUC) x (GFR + 25), where AUC = area under the curve and GFR = glomerular filtration rate.

Physician's Choice of Salvage Therapy - carboplatin

Nicholas Butowski, M.D.

This is an adaptive design, randomized controlled, Phase 3 clinical trial in patients with glioblastoma multiforme (GBM) or gliosarcoma (GS), previously treated with surgery (if appropriate), standard of care chemo-radiation with temozolomide, +/- adjuvant temozolomide, and bevacizumab and now has progressive disease during or after bevacizumab.

A total of up to 180 eligible patients with recurrent/progressive GBM or GS will be randomized to receive either the investigational drug (VAL-083) or "Investigator's choice of salvage therapy" as a contemporaneous control, in a 2:1 fashion. Up to 120 eligible patients will be randomized to receive VAL-083 at 40 mg/m2 IV on days 1, 2, and 3 of a 21-day treatment-cycle, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation. Up to 60 patients will be randomized to receive "Investigator's choice of salvage therapy", limited to temozolomide, lomustine, or carboplatin, until they fulfill one of the criteria for study discontinuation. The dose level for Investigator's choice salvage therapy (temozolomide, lomustine, or carboplatin), will be in accordance with the product label or institutional guidelines.

In both study arms, interval medical histories, targeted physical exams, neurologic evaluations, complete blood counts, and other laboratory and safety assessments will be performed approximately every 21-days while receiving treatment. Tumor assessments are to be performed approximately every 42 ± 7 days while remaining on study. The study is estimated to last approximately 20 months.

This is an adaptive, randomized controlled, Phase 3 clinical trial in adult patients with histologically confirmed diagnosis of a recurrent glioblastoma multiforme (GBM) or gliosarcoma (GS), who have been previously treated with surgery (if appropriate), standard of care chemo-radiation with temozolomide, +/- adjuvant temozolomide, and bevacizumab and now have progressive disease during or after bevacizumab. Patients with prior low-grade glioma or anaplastic glioma are eligible, if histologic assessment demonstrates transformation to GBM or GS.

Treatment Groups: Eligible patients will be randomized to receive either the investigational drug (VAL-083) or "Investigator's choice of salvage therapy" as a contemporaneous control, in a 2:1 fashion. A total of up to 180 patients with recurrent/progressive GBM or GS will be enrolled; patients will be randomized to one of two treatment arms as follows:

Group 1: Up to 120 eligible patients will be randomized to receive VAL-083 at 40 mg/m2 IV on days 1, 2, and 3 of a 21-day treatment-cycle, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation (death, intolerable toxicities, investigator's judgment, or withdrawal of consent). In patients who demonstrate response, stable disease or who continue therapy at the discretion of the investigator following initial progression and tolerate therapy, permission to continue treatment beyond 12 cycles will be considered but will require consent of the Sponsor. VAL-083 will be administered as an IV infusion over 30-60 minutes.

Group 2: Up to 60 patients will be randomized to receive "Investigator's choice of salvage therapy" until they fulfill one of the criteria for study discontinuation (death, intolerable toxicities, investigator's judgment, or withdrawal of consent). "Investigator's choice of salvage therapy" will be limited to the following: temozolomide, lomustine, or carboplatin. The dose level for Investigator's choice salvage therapy (temozolomide, lomustine, or carboplatin), will be in accordance with the product label or institutional guidelines.

In both arms, disease status will be evaluated with clinical and imaging evaluation. Baseline total tumor burden must be assessed by MRI within 2 weeks prior to randomization. For patients randomized to VAL-083, post-baseline tumor assessments are to be performed prior to every other 21-day cycle for VAL-083, i.e., prior to Cycles 3, 5, etc., while the patient is receiving VAL-083 treatment, and then approximately every 42 ± 7 days while remaining on study. For patients randomized to the Physician's choice salvage therapy arm, post-baseline tumor assessments are to be performed approximately every 42 ± 7 days while remaining on study, as long as the patient continues to demonstrate response or stable disease or comes off the study.

In both study arms, assessments will include interval medical histories, Karnofsky Performance Status, physical and neurological examinations, vital signs, weight, adverse events, hematology and serum biochemistry, pregnancy test (females), urinalysis, chest x-ray and EKG approximately every 21-days while receiving treatment, as well as MDASI-BT self-reporting assessment when MRI tumor measurements are performed.

In a subgroup of 60 study subjects receiving VAL-083, blood samples will be obtained to determine population pharmacokinetics at pre-dose Cycle 1 Day 1, then at post-infusion on Cycle 1 Day 1, Cycle 1 Day 3, Cycle 2 Day 1 and Cycle 3 (or Cycle 4) Day 1 (or Day 3) in accordance with the study subject's assigned sampling block. EKGs will be taken pre-dose and approximately 10 minutes post-infusion Cycle 1 Day 1, prior to the 15 min (15 ± 5 min) blood draw for PK assessment, as well as pre-dose and approximately 10 minutes post-infusion Cycle 1 Day 3, prior to the 15 min (15 ± 5 min) blood draw for PK.

In a separate sub-group of 15 study subjects receiving VAL-083, blood will be drawn from Cycle 1 Day 1 and Cycle 1 Day 3 of dosing for determination of plasma levels of VAL-083 over the first 6 hours after the end of infusion (i.e., 0.25, 0.5, 1, 2, 4 and 6 hr). Trough levels 24 hr after infusion will also be obtained in these subjects. EKGs will be taken pre-dose and approximately 10 minutes post-infusion Cycle 1 Day 1, prior to the 15 min (15 ± 5 min) blood draw for PK assessment, as well as pre-dose and approximately 10 minutes post-infusion Cycle 1 Day 3, prior to the 15 min (15 ± 5 min) blood draw for PK.

Patients will be followed until death to ensure adequate power (90%) for the primary analysis.

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

Quality of life will be evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT). This questionnaire will be completed by patients at baseline and at the time of each imaging evaluation, until progression.

The study is estimated to take approximately 20 months, including 18 months to enroll 180 patients and another 2 months to reach 125 events (deaths).

VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM

A Pivotal Randomized, Controlled Trial of VAL-083 in Patients With Recurrent Glioblastoma Who Have Failed Standard Temozolomide/Radiation Therapy and Bevacizumab (STAR-3)

The Clinical Study Report for this trial will be prepared upon completion of trial 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. Data will include overall survival (OS), progression-free survival (PFS) at 6 months, median PFS, OS at 6 and 9 months, overall response rate (ORR), duration of response (DOR), disease control rate (DCR), occurrence of disease symptoms and evaluation of quality of life (QOL) measures during the progression-free period for VAL-083, compared to Investigator choice salvage therapy. Also, the safety and toxicity profile as well as pharmacokinetics of VAL-083 will be summarized.

Time from patient randomization to patient death

Time from patient randomization to first occurrence of disease progression (per RANO criteria) or death, whichever occurs first.

Time from the patient's first occurrence of a documented, objective response (confirmed Complete Response or Partial Response) until the time of relapse (per RANO criteria) or death from any cause

Time from patient randomization through 28 days following last study treatment received by patient. Safety will be assessed through summaries of AEs, changes in laboratory test results, ECGs, and changes in vital signs for all patients who receive any amount of VAL-083 or Physician's choice salvage therapy

Maximum observed plasma concentration of VAL-083 in a sub-group of 15 study subjects receiving VAL-083

Time of maximum observed plasma concentration of VAL-083 in a sub-group of 15 study subjects receiving VAL-083

Area under the concentration-time curve from pre-dose (time 0) to the time of the last quantifiable concentration of VAL-083 in plasma for a sub-group of 15 study subjects receiving VAL-083

Area under the concentration-time curve extrapolated to infinity for VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

Total oral body clearance at steady state for VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

AUMC/AUC for VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083, where AUMC is Area Under the Moment Curve

Volume of distribution during the terminal phase of VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

Terminal elimination rate constant determined by selection of at least 3 decreasing data points on the terminal phase of the concentration-time curve for VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

Terminal elimination half-life of VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

Evaluate patient quality of life from time of patient randomization to first occurrence of disease progression (per RANO criteria) or death, whichever occurs first.

DelMar Pharmaceuticals, Inc.

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.

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).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM	NCT03149575	Glioblastoma Mu... Glioblastoma Glioma GBM Brain Cancer	VAL-083, Dianhy... Physician's Cho... Physician's Cho... Physician's Cho...	18 Years -	Kintara Therapeutics, Inc.
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.

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