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

This study is currently recruiting participants.
Verified October 2017 by DelMar Pharmaceuticals, Inc.
Sponsor:
ClinicalTrials.gov Identifier:
NCT03149575
First Posted: May 11, 2017
Last Update Posted: October 20, 2017
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.
Information provided by (Responsible Party):
DelMar Pharmaceuticals, Inc.
  Purpose

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.


Condition Intervention Phase
Glioblastoma Multiforme Glioblastoma Glioma GBM Brain Cancer Drug: VAL-083, Dianhydrogalactitol Drug: Physician's Choice of Salvage Therapy - temozolomide Drug: Physician's Choice of Salvage Therapy - lomustine Drug: Physician's Choice of Salvage Therapy - carboplatin Phase 3

Access to an investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pivotal Randomized, Controlled Trial of VAL-083 in Patients With Recurrent Glioblastoma Who Have Failed Standard Temozolomide/Radiation Therapy and Bevacizumab (STAR-3)

Resource links provided by NLM:


Further study details as provided by DelMar Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • Overall Survival [ Time Frame: Assessed approximately every 42 days for duration of study participation which is estimated to be 12 months ]
    Time from patient randomization to patient death


Secondary Outcome Measures:
  • Progression Free Survival [ Time Frame: Assessed approximately every 42 days for duration of study participation which is estimated to be 12 months ]
    Time from patient randomization to first occurrence of disease progression (per RANO criteria) or death, whichever occurs first.

  • Duration of Response [ Time Frame: Assessed approximately every 42 days for duration of study participation which is estimated to be 12 months ]
    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

  • Incidence of Treatment-Emergent Adverse Events (Overall Safety and Toxicity) [ Time Frame: Assessed approximately every 42 days for duration of study participation which is estimated to be 12 months ]
    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

  • Cmax [ Time Frame: Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2. ]
    Maximum observed plasma concentration of VAL-083 in a sub-group of 15 study subjects receiving VAL-083

  • Tmax [ Time Frame: Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2. ]
    Time of maximum observed plasma concentration of VAL-083 in a sub-group of 15 study subjects receiving VAL-083

  • AUClast [ Time Frame: Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2. ]
    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

  • AUCinf [ Time Frame: Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2. ]
    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

  • CL/F [ Time Frame: Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2. ]
    Total oral body clearance at steady state for VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

  • Mean Residence Time [ Time Frame: Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2. ]
    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

  • Vz [ Time Frame: Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2. ]
    Volume of distribution during the terminal phase of VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

  • Lambda z [ Time Frame: Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2. ]
    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

  • T 1/2 [ Time Frame: Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2. ]
    Terminal elimination half-life of VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

  • Quality of Life [ Time Frame: Assessed approximately every 42 days for duration of study participation which is estimated to be 12 months ]
    Evaluate patient quality of life from time of patient randomization to first occurrence of disease progression (per RANO criteria) or death, whichever occurs first.


Estimated Enrollment: 180
Anticipated Study Start Date: November 2017
Estimated Study Completion Date: August 2019
Estimated Primary Completion Date: June 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: VAL-083, Dianhydrogalactitol
Up to 120 eligible patients will be randomized to receive VAL-083.
Drug: VAL-083, Dianhydrogalactitol
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
Active Comparator: Physician's Choice of Salvage Therapy
Up to 60 patients will be randomized to receive "Investigator's choice of salvage therapy" temozolomide, lomustine, or carboplatin
Drug: Physician's Choice of Salvage Therapy - temozolomide

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.

Drug: Physician's Choice of Salvage Therapy - lomustine

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.

Drug: Physician's Choice of Salvage Therapy - carboplatin

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.


  Show Detailed Description

  Eligibility

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.


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

Inclusion Criteria:

  1. Patient must agree to testing of GBM tumor promoter methylation status of the MGMT gene and tumor (IDH1) gene mutation status. Tissue may be tested at study entry, if not done previously, or data may be obtained from last known test result for MGMT and IDH1. IDH1 status may be assessed at study entry, but MGMT status is required prior to randomization.
  2. Agree to allow the sponsor to collect data on all GBM-related treatments received after the patient comes off the current study, and to collect survival data after the patient comes off the current study.
  3. Patient must be ≥ 18 years old.
  4. Histologically confirmed initial diagnosis of primary glioblastoma multiforme (GBM) or gliosarcoma (GS), now recurrent. Patients with recurrent/progressive disease whose initial diagnostic pathology confirmed GBM or GS will not need re-biopsy. Patients with prior low-grade glioma or anaplastic glioma are eligible, if histologic assessment demonstrates transformation to GBM or GS.
  5. Patient has previously received standard of care chemo-radiation with temozolomide, ± adjuvant temozolomide and bevacizumab and now has radiographic evidence of recurrent/progressive GBM or GS during or after bevacizumab.
  6. Patient must have bi dimensionally measurable disease, per the proposed Response Assessment in NeuroOncology (RANO; Appendix C) (Wen et al., 2010), with measurement of >1 cm in one diameter and ≤5 cm diameter in any plane on MRI performed within 2 weeks prior to randomization.
  7. At least 4 weeks from last chemotherapy or bevacizumab (Avastin®) therapy (6 weeks for nitrosourea or mitomycin C), or for chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity, at least 2 weeks from last dose.
  8. If the patient has been using the Optune™ device, it will be discontinued at least four days prior to commencing treatment with VAL-083, and the patient must have recovered from all treatment-related toxicities to Grade 1 or less.
  9. Baseline MRI must be obtained ≥ 4 weeks after surgical resection but within 2 weeks prior to randomization.
  10. Adequate recovery from all recent surgery is required; at least 1 week must have elapsed from the time of a minor surgery; at least 21 days must have elapsed from the time of a major surgery. Patients must have recovered from all surgery-related toxicities to Grade 1 or less.
  11. 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.
  12. Greater than 12 weeks from radiotherapy, to minimize the potential for MRI changes related to radiation necrosis that might be misdiagnosed as pseudoprogression of disease, unless the recurrence is a new lesion, outside the primary radiation field or the patient fulfills criteria for early progressive disease by RANO ((Wen et al., 2010); Appendix C).
  13. 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 post-radiotherapy histologic documentation of recurrence in the irradiated field, unless the recurrence is a new lesion outside the irradiated field.
  14. If receiving corticosteroids, patients must be on a stable or decreasing dose of corticosteroids for ≥ 5 days prior to baseline MRI.
  15. At least 28 days or 5 half-lives (whichever is shorter) since prior investigational anti-cancer drugs. A minimum of 21 days between termination of the investigational drug and administration of VAL-083 is required.
  16. Must have recovered from all treatment-related toxicities to Grade 1 or less.
  17. Patients must have a Karnofsky performance status (KPS; Appendix D) of ≥ 70%
  18. KPS must have been stable during the period from wash-out of prior therapy to randomization. A declining KPS is defined by reduction of 10 points or more over at least a 28-day period.
  19. Patient must have a predicted life expectancy of at least 12 weeks.
  20. Laboratory values as follows at screening and within 7 days of planned first dose of therapy:

    1. Absolute neutrophil count (ANC) ≥1500/μL.
    2. Hemoglobin (HgB) ≥9 g/dL.
    3. Platelets ≥100,000/μL (≥150,000/μL, if within 12 weeks of prior nitrosourea treatment).
    4. Serum creatinine ≤1.5 x upper limit of normal or creatinine clearance >60 mL/min (measured or calculated by the Cockcroft-Gault formula) (Cockcroft DW et al, 1976).
    5. AST, ALT must be <2 x ULN.
    6. Total bilirubin <1.5 x the institutional ULN, unless the subject has documented unconjugated bilirubin disorder such as Gilbert's syndrome.
    7. Subjects with known Gilbert's syndrome who have serum bilirubin ≤ 3 x ULN (NCI CTCAE v4.03 Grade 2) may be enrolled.
    8. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 x the ULN.
    9. QTc <450 msec on screening ECG.
  21. No clinically significant cardiac conduction disorder on screening.
  22. Female patients of child-bearing potential must have a negative serum or urine pregnancy test within 7 days prior to planned first dose of treatment, and agree to use dual method of contraception through 90 days after study drug treatment. Approved methods of contraception include an IUD with spermicide, a female condom with spermicide, a diaphragm with spermicide, a cervical cap with spermicide, use of a condom with spermicide by sexual partner or a sterile sexual partner. Women of childbearing potential are defined to include any female who:

    1. Has experienced menarche and has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy); and
    2. Is not post-menopausal (defined as amenorrhea >12 consecutive months).
  23. If male, patient must be sterile or willing to use an approved method of contraception from the time of Informed Consent to 90 days after study drug treatment. Males must be willing to refrain from sperm donation within 90 days after study treatment.

Exclusion Criteria:

  1. Current history of neoplasm other than the entry diagnosis. Exceptions are:

    1. Curatively treated basal cell/squamous cell skin cancer
    2. Carcinoma in situ of the cervix
    3. Patients with previous solid and hematologic tumors, that have been treated with no evidence of recurrence within the last 5 years, are permitted.
  2. Evidence of diffuse subependymal disease or tumor in the brainstem, cerebellum, spinal cord, or CSF.
  3. Radiological evidence of multifocal disease, tumors extending into or crossing the corpus callosum or leptomeningeal disease.
  4. Need for urgent palliative intervention for primary disease (e.g., impending herniation).
  5. Evidence of recent hemorrhage on baseline MRI of the brain with the following exceptions:

    1. Presence of hemosiderin.
    2. Resolving hemorrhagic changes related to surgery.
    3. Presence of punctate hemorrhage in the tumor.
  6. Concurrent 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.
  7. Any of the following cardiac conditions:

    1. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, and/or stenting up to 12 weeks before Cycle 1, Day 1.
    2. Class III or IV heart failure as defined by the New York Heart Association functional classification system up to 6 months before Cycle 1, Day 1.
  8. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of treatment.
  9. History of stroke or transient ischemic attack within 6 months prior to beginning treatment.
  10. Patients receiving prohibited concomitant medications at the start of the study
  11. Patients with steroid myopathy.
  12. Patients who are HIV positive with an active AIDS-related illness are excluded; patients who are HIV positive but on stable therapy are not excluded.
  13. Patients with a known sensitivity to any of the products to be administered during treatment and assessments.
  14. Women who are pregnant or lactating.
  15. Patients unable to undergo an MRI of the brain with contrast.
  Contacts and Locations
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): NCT03149575


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

Locations
United States, California
University of California, San Francisco - Division of Neuro-Oncology Not yet recruiting
San Francisco, California, United States, 94143
Contact: Nicholas Butowski, M.D.    415-353-2966      
Principal Investigator: Nicholas Butowski, M.D.         
United States, New Jersey
Atlantic Neuroscience Institute - Brain Tumor Center of NJ Not yet recruiting
Summit, New Jersey, United States, 07901
Contact: Kurt A Jaeckle, M.D.    908-522-5914      
Principal Investigator: Kurt A Jaeckle, M.D.         
United States, New York
Dent Neurosciences Research Center Recruiting
Amherst, New York, United States, 14226
Contact: Laszlo Mechtler, M.D.    716-250-2000      
Principal Investigator: Laszlo Mechtler, M.D.         
Sponsors and Collaborators
DelMar Pharmaceuticals, Inc.
Investigators
Principal Investigator: Nicholas Butowski, M.D. University of California, San Francisco, California, USA 94143
  More Information

Responsible Party: DelMar Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03149575     History of Changes
Other Study ID Numbers: DLM-16-002
First Submitted: May 3, 2017
First Posted: May 11, 2017
Last Update Posted: October 20, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: 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.

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

Keywords provided by DelMar Pharmaceuticals, 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 temodar
failed temozolomide
temodar refractory
temozolomide refractory
failed avastin
avastin refractory
failed bevacizumab
bevacizumab refractory
avastin failure
bevacizumab failure
STAR-3

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
Bevacizumab
Temozolomide
Carboplatin
Dacarbazine
Lomustine
Dianhydrogalactitol
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antineoplastic Agents, Alkylating