Safety Study of VAL-083 and Radiotherapy in Patients With Newly Diagnosed GBM Having Unmethylated MGMT Expression

• ClinicalTrials.gov Identifier: NCT03050736
• Recruitment Status: Recruiting
• First Posted: February 13, 2017
• Last Update Posted: May 24, 2019
• Sponsor: DelMar Pharmaceuticals, Inc.
• Collaborator: Sun Yat-sen University
• Information provided by (Responsible Party): DelMar Pharmaceuticals, Inc.

Study Description

Brief Summary:

The purpose of this Phase 2, open-label, single-arm study is to determine the safety and the maximal tolerated dose (MTD) of VAL-083 in combination with a standard of care radiation regimen when used to treat newly diagnosed GBM in patients with unmethylated promoter of the methylguanine-DNA methyltransferase (uMGMT) gene. Pharmacokinetic (PK) properties will be explored and tumor responses to treatment will be evaluated.

Condition or disease	Intervention/treatment	Phase
Glioma; Glioblastoma; Glioblastoma Multiforme; GBM; Brain Cancer	Drug: VAL-083 (Dianhydrogalactitol)	Phase 2

  Show Detailed Description

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Trial of Dianhydrogalactitol (VAL-083) and Radiation Therapy in Treatment of Newly Diagnosed GBM Patients With An Unmethylated Promoter of the Methylguanine-DNA Methyltransferase (MGMT) Gene
• Actual Study Start Date: December 17, 2017
• Estimated Primary Completion Date: December 2019
• Estimated Study Completion Date: June 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: VAL-083 (Dianhydrogalactitol); VAL-083 given by intravenous infusion with a starting dose of 20 mg/m2 IV. Escalating doses to be administered in sequential dose cohorts.	Drug: VAL-083 (Dianhydrogalactitol); VAL-083 given by intravenous infusion with a starting dose of 20 mg/m2 IV. Escalating doses to be administered in sequential dose cohorts.

Outcome Measures

Primary Outcome Measures :

1. Efficacy evaluation of tumor response in patients, as measured by magnetic resonance imaging [ Time Frame: Every 42 days while receiving radiotherapy then every 63 days while remaining on study, from patient randomization until study discontinuation for up to 10 months ]
   Tumor response assessment via MRI, as long as patient continues to demonstrate response or stable disease and tolerates therapy.

Secondary Outcome Measures :

1. Safety evaluation of VAL-083 in combination with a standard radiation therapy, as determined by incidence of patient adverse events and changes in laboratory results, ECG and vital signs [ Time Frame: Every 30 days, from patient randomization through 28 days following last study treatment for up to 10 months ]
   To confirm the safety and tolerability of VAL-083 in combination with a standard of care radiation regimen. 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.
2. Ctrough [ Time Frame: On Cycle 1 Day 1 pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration then Cycle 1 Day 2 pre-dose ]
   Pre-dose plasma concentration of VAL-083
3. Cmax [ Time Frame: On Cycle 1 Day 1 pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration then Cycle 1 Day 2 pre-dose ]
   Maximum observed plasma concentration of VAL-083
4. Tmax [ Time Frame: On Cycle 1 Day 1 pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration then Cycle 1 Day 2 pre-dose ]
   Time of observed Cmax for VAL-083 in plasma
5. AUClast [ Time Frame: On Cycle 1 Day 1 pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration then Cycle 1 Day 2 pre-dose ]
   Area under the concentration-time curve from pre-dose (time 0) to the time of the last quantifiable concentration of VAL-083 in plasma
6. AUCinf [ Time Frame: On Cycle 1 Day 1 pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration then Cycle 1 Day 2 pre-dose ]
   Area under the concentration-time curve extrapolated to infinity for VAL-083 in plasma
7. CL/F [ Time Frame: On Cycle 1 Day 1 pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration then Cycle 1 Day 2 pre-dose ]
   Total oral body clearance at steady state for VAL-083 in plasma
8. Mean Residence Time [ Time Frame: On Cycle 1 Day 1 pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration then Cycle 1 Day 2 pre-dose ]
   AUMC/AUC for VAL-083 in plasma, where AUMC is Area under the Moment Curve
9. Vz [ Time Frame: On Cycle 1 Day 1 pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration then Cycle 1 Day 2 pre-dose ]
   Volume of distribution during the terminal phase of VAL-083 in plasma
10. Lambda z [ Time Frame: On Cycle 1 Day 1 pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration then Cycle 1 Day 2 pre-dose ]
    Terminal elimination rate constant determined by selection of at least three decreasing data points on the terminal phase of the concentration-time curve for VAL-083 in plasma
11. T½ [ Time Frame: On Cycle 1 Day 1 pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration then Cycle 1 Day 2 pre-dose ]
    Terminal elimination half-life of VAL-083 in plasma
12. Pharmacokinetic profile and dose-exposure relationship of VAL-083 in Cerebral Spinal Fluid (CSF) [ Time Frame: Once after completion of Cycle 1 Day 3 infusion ]
    VAL-083 levels in CSF will be correlated with VAL-083 levels in plasma drawn at Cycle 1 Day 3.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 69 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Newly diagnosed histologically proven supratentorial GBM
2. Tumor tissue specimens from the GBM surgery or open biopsy must be available for MGMT gene promoter status analysis and central pathology review.
3. Documented unmethylated MGMT gene promoter status
4. Males or females ≥18< 70 years of age.
5. Interval of ≥2 weeks but ≤7 weeks after surgery or biopsy before first administration of study treatment.
6. Cranial MRI must have been performed within 21 days of study entry and MRI must be used throughout the period of protocol treatment for tumor measurement. If the surgical procedure was a resection, cranial MRI performed within 72 hours of resection is preferred
7. Stable or decreasing dose of steroids for ≥5 days prior to randomization.
8. Karnofsky performance score ≥ 70%
9. Patients must begin treatment with VAL-083 chemotherapy no sooner than 2 weeks and no later than 4 weeks from the diagnostic surgery.
10. ANC ≥1,500/ µl
11. Platelet count ≥ 100,000/µl
12. Hemoglobin ≥ 10 gm/dl
13. AST, ALT < 2.5 times ULN
14. Bilirubin < 2.5 ULN
15. Serum creatinine ≤ 1.5x ULN or creatinine clearance > 50 mL/min (measured or calculated by the Cockcroft-Gault formula) (Cockcroft, 1976) at screening

Exclusion Criteria:

1. Prior chemotherapy within the last 5 years.
2. Prior radiation therapy of the head.
3. Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of VAL-083.
4. Prior systemic anti-angiogenic therapy.
5. Placement of Gliadel® wafer at surgery.
6. Planned surgery for other diseases (e.g. dental extraction).
7. History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal ulcer, or esophageal ulcer) within 6 months of enrollment.
8. History of malignancy. Subjects with curatively treated cervical carcinoma in situ or basal cell carcinoma of the skin, or subjects who have been free of other malignancies for ≥5 years are eligible for this study.
9. History of coagulation disorder associated with bleeding or recurrent thrombotic events.
10. Clinically manifest myocardial insufficiency (New York Heart Association [NYHA] III, IV) or history of myocardial infarction during the past 6 months; or uncontrolled arterial hypertension.
11. Inability to undergo Gd-MRI.
12. Concurrent illness, including severe infection, which may jeopardize the ability of the subject to receive the procedures outlined in this protocol with reasonable safety.
13. Subject is pregnant (positive serum beta human chorionic gonadotropin [b-HCG] test at screening) or is currently breast-feeding, anticipates becoming pregnant/ impregnating their partner during the study or within 6 months after study participation, or subject does not agree to follow acceptable methods of birth control, such as hormonal contraception, intra-uterine pessar, condoms or sterilization, to avoid conception during the study and for at least 6 months after receiving the last dose of study treatment.
14. Current alcohol dependence or drug abuse.
15. Known hypersensitivity to the study treatment.
16. Legal incapacity or limited legal capacity.
17. Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
18. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such.

Contacts and Locations

Contacts

Contact: Chen Zhong-ping, M.D., Ph.D.; +86 (20) 87343310; chenzhp@sysucc.org.cn

Contact: John Langlands, Ph.D.; 604-629-5989; jlanglands@delmarpharma.com

Locations

China

Sun Yat-Sen University Cancer Center; Recruiting

Guangzhou, China, 510060

Contact: Chen Zhong-ping, M.D., Ph.D. +86 (20) 87343310 chenzhp@sysucc.org.cn

Sponsors and Collaborators

DelMar Pharmaceuticals, Inc.

Sun Yat-sen University

Investigators

• Principal Investigator: Chen Zhong-ping, M.D., Ph.D.; Sun Yat-sen University

More Information

• Responsible Party: DelMar Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03050736 History of Changes
• Other Study ID Numbers: DLM-14-001
• First Posted: February 13, 2017
• Last Update Posted: May 24, 2019
• Last Verified: February 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: 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). The trial investigator will be provided a copy of their patient data captured in the electronic data base for this trial.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by DelMar Pharmaceuticals, Inc.:

Glioma; Glioblastoma; Glioblastoma multiforme; GBM; brain tumor; brain cancer

Additional relevant MeSH terms:

Glioblastoma; Glioma; Brain Neoplasms; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dianhydrogalactitol; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents