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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02717962
Recruitment Status : Recruiting
First Posted : March 24, 2016
Last Update Posted : October 1, 2020
Sponsor:
Information provided by (Responsible Party):
Kintara Therapeutics, Inc.

Brief Summary:
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.

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

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Detailed Description:

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 24 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 107 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study of VAL-083 Treatment for MGMT Unmethylated Bevacizumab-naïve Glioblastoma in the Adjuvant or Recurrent Setting
Actual Study Start Date : January 20, 2017
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: VAL-083, Dianhydrogalactitol (Group 1)
Patients with recurrent/progressive GBM
Drug: VAL-083, Dianhydrogalactitol
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.

Experimental: VAL-083, Dianhydrogalactitol (Group 2)
Newly diagnosed GBM patients who have completed chemoradiation treatment with temozolomide and received no subsequent maintenance temozolomide
Drug: VAL-083, Dianhydrogalactitol
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.




Primary Outcome Measures :
  1. Overall Survival [ Time Frame: Every 30 days from randomization until patient death ]
    Length of time from start of treatment (Day 1) until patient death


Secondary Outcome Measures :
  1. Estimate Progression-free Survival [ Time Frame: Every 30 days from randomization until disease progression or patient death, whichever occurs earlier ]
    Time from start of treatment (Day 1) until to the first occurrence of progression or patient death, whichever occurs first

  2. Estimate Median Progression-Free Survival [ Time Frame: Every 30 days from randomization until disease progression or patient death, whichever occurs earlier ]
    The median length of time from start of treatment (Day 1) until to the first occurrence of progression or patient death, whichever occurs first

  3. Estimate Median Overall Survival [ Time Frame: Every 30 days from randomization until patient death ]
    The median length of time from start of treatment (Day 1) until patient death

  4. Estimate Overall Response Rate [ Time Frame: Every 42 days from randomization to achievement of either complete response (CR) or partial response (PR) ]
    Overall number of tumor complete response (CR) or partial response (PR) determined via MRI assessment

  5. Estimate Duration of Response [ Time Frame: Every 42 days from the first occurrence of a documented, objective response until the time of relapse or patient death ]
    Length of time tumor continues to demonstrate either complete response (CR) or partial response (PR) via MRI assessment

  6. Safety evaluation of VAL-083 in patients [ Time Frame: From randomization up to 28 days following last study treatment ]
    To confirm safety and tolerability of VAL-083 using NCI CTCAE v.4 to assess adverse events

  7. Quality of Life [ Time Frame: Every 42 days from randomization until disease progression ]
    MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT)

  8. Plasma Pharmacokinetics [ Time Frame: Cycle 1 Day 1 predose, 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 of VAL-083 ]
    PK profile and dose-exposure relationship of VAL-083



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

General Inclusion Criteria:

  • Patient must willingly provide written consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.
  • Patients must be ≥ 18 years old.
  • Patients must have histologically confirmed initial diagnosis of primary intracranial WHO Grade IV malignant glioma (glioblastoma).
  • Patients must have preliminary GBM MGMT status (tumor must be MGMT promoter unmethylated) determined prior to study entry. If initial MGMT status is determined to be "unmethylated", by an outside institution the patient may be enrolled and begin treatment. However, MGMT status must be retested following enrollment by central laboratory CLIA certified testing at MD Anderson.
  • Patients must have Karnofsky Performance Status (KPS) > 60% (i.e., 70, 80, 90 or 100).
  • Adequate recovery from all recent surgery is required. At least 21-days must have elapsed from the time of any major surgery, including craniotomy/tumor resection. Patients must have recovered from all surgery-related toxicities to Grade 1 or less.
  • Prior therapy with gamma knife or other focal high-dose radiation is allowed, but at least 2 weeks must have elapsed from the time of treatment, and the patient must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field.
  • Patients having prior therapy with Laser Induced Thermal Therapy (LITT) is allowed, but at least 21 days must have elapsed from last LITT, with recovery from all LITT-related toxicities to Grade 1 or less and subsequent histologic documentation of recurrence
  • Patients must be at least 4 weeks from last dose of chemotherapy.
  • Patients must have recovered from all treatment-related toxicities to Grade 1 or less.
  • If receiving corticosteroids, patients must be on a stable or decreasing dose of corticosteroids for ≥ 5 days prior to baseline MRI.
  • Patients must have a predicted life expectancy of at least 12 weeks.
  • Patients must have adequate bone marrow and organ function.
  • Patients must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests and accessible for follow-up after treatment termination.
  • If the patient has been using the Optune™ device, it will be discontinued before initiating treatment with either study medication, and per inclusion criterion listed above, the patient must have recovered from all treatment-related toxicities to Grade 1 or less.
  • Pregnancy restrictions - Women of childbearing potential must have a negative B-HCG documented within 7 days prior to registration

Group Specific Inclusion Criteria - Recurrent GBM (Group 1):

  • Patients must have recurrent disease whose initial diagnostic pathology confirmed glioblastoma will not need re-biopsy. Alternately, patients with prior intracranial low-grade glioma or anaplastic glioma will be eligible, if histologic assessment demonstrates transformation to GBM (first diagnosis of secondary GBM).
  • Patients must have radiographic evidence of recurrent/progressive GBM after prior therapy (biopsy or resection and chemoradiation); 1st recurrence of GBM only, per RANO criteria. Histologically documented transformation from a lower grade gliomas will be considered first recurrence.
  • Patients must be >12 weeks from radiotherapy, to minimize the potential for MRI changes related to treatment (pseudoprogression) that might be misdiagnosed as true progression of disease, unless the patient fulfills criteria for early progressive disease by RANO.
  • Patients must have been previously treated for GBM with concurrent temozolomide and radiation followed by adjuvant temozolomide chemotherapy.
  • Patients must be at least 4 weeks or 5 half-lives (whichever is shorter) from the last dose of prior investigational anti-cancer drugs.

Group Specific Inclusion Criteria - Newly Diagnosed GBM requiring maintenance therapy (Group 2)

  • Patients must not have recurrent disease.
  • Patients must be < 6 weeks from radiotherapy to start of treatment with VAL-083.
  • Patients must have been previously treated for GBM with concurrent temozolomide and radiation, and received no subsequent maintenance temozolomide chemotherapy.
  • No prior investigational agent.

Exclusion Criteria:

  • Within 12 weeks of chemoradiation unless the patient fulfills criteria for early progressive disease by RANO, for Group 1; and, more than 6 weeks from chemoradiation for Group 2.
  • Receipt of investigational agents within 5 half-lives of last dose of investigational agent.
  • Concurrent use of other investigational agents or Optune™ device
  • Prior therapy with lomustine.
  • Prior therapy with bevacizumab.
  • Current history of neoplasm other than the entry diagnosis. Patients with previous cancers treated and cured with local therapy alone may be considered with approval of the Sponsor.
  • Evidence of leptomeningeal spread of disease.
  • Need for urgent palliative intervention (e.g., impending herniation).
  • Severe, intercurrent illness including, but not limited to unstable systemic disease, including ongoing or active infection, uncontrolled hypertension, serious cardiac arrhythmia requiring medication, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients with a known sensitivity to any of the products to be administered during treatment.
  • Patients unable to undergo MRI of the brain.
  • Women who are pregnant or lactating. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment. Women of childbearing potential or men with partners of childbearing potential must use effective birth control measures during treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02717962


Contacts
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Contact: Lorena Lopez, B.S. 925-292-8360 llopez@solsentinel.com
Contact: John Langlands, Ph.D. 604-629-5989 jlanglands@kintara.com

Locations
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United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Stephanie Knight, B.S.N., R.N.    713-563-8746    SRKnight@mdanderson.org   
Principal Investigator: Barbara O'Brien, M.D.         
Sub-Investigator: Marta Penas-Prado, M.D.         
Sub-Investigator: Rivkah Cohen, M.D.         
Sub-Investigator: Carlos Kamiya-Matsuoka, M.D.         
Sub-Investigator: John DeGroot, M.D.         
Sub-Investigator: Monica Loghin, M.D.         
Sub-Investigator: Shiao-Pei Weathers, M.D.         
Sub-Investigator: W.K. Alfred Yung, M.D.         
Sub-Investigator: Greg Fuller, M.D.         
Sub-Investigator: Rebecca Harrison, M.D         
Principal Investigator: Nazanin Majd, M.D         
Sponsors and Collaborators
Kintara Therapeutics, Inc.
Investigators
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Principal Investigator: Barbara O'Brien, M.D. University of Texas, MDAnderson Cancer Center, Houston, Texas, USA 77030
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Responsible Party: Kintara Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT02717962    
Other Study ID Numbers: DLM-16-001
First Posted: March 24, 2016    Key Record Dates
Last Update Posted: October 1, 2020
Last Verified: September 2020
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). Each participating trial investigator will be provided a copy their patient data captured in the electronic data base for this trial.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kintara Therapeutics, Inc.:
Glioma
Glioblastoma
Glioblastoma multiforme
GBM
brain tumor
brain cancer
recurrent brain tumor
recurrent brain cancer
refractory brain tumor
refractory brain cancer
recurrent GBM
refractory GBM
recurrent glioma
refractory glioma
recurrent glioblastoma
refractory glioblastoma
recurrent glioblastoma multiforme
refractory glioblastoma multiforme
failed bevacizumab
temodar failure
temozolomide failure
adjuvant therapy
Additional relevant MeSH terms:
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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