Vaccine Therapy, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

• ClinicalTrials.gov Identifier: NCT01222221
• Recruitment Status: Completed
• First Posted: October 18, 2010
• Last Update Posted: October 14, 2015
• Sponsor: Cancer Research UK
• Collaborator: Immatics Biotechnologies GmbH
• Information provided by (Responsible Party): Cancer Research UK

Study Description

Brief Summary:

RATIONALE: Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vaccine therapy together with temozolomide and radiation therapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects of vaccine therapy when given together with temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma multiforme.

Condition or disease	Intervention/treatment	Phase
Brain and Central Nervous System Tumors	Biological: glioblastoma multiforme multipeptide vaccine IMA950; Biological: sargramostim; Drug: temozolomide; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: adjuvant therapy; Radiation: radiation therapy	Phase 1

Detailed Description:

OBJECTIVES:

Primary

• To assess the safety and tolerability of glioblastoma multiform multi-antigen vaccine IMA950 plus sargramostim (GM-CSF) in combination with standard chemoradiotherapy comprising temozolomide and radiotherapy followed by adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.
• To determine the immunogenicity of this regimen in these patients.

Secondary

• To determine the anti-tumor effect of this regimen in these patients.
• To determine the effect of pre-treatment levels of regulatory T-cells on the immunogenicity of this regimen in these patients. (Exploratory)
• To evaluate the potential effect of steroid dose on the immunological response to glioblastoma multiform multi-antigen vaccine IMA950 plus GM-CSF.

Tertiary

• To assess the level of O6-methyl-DNA-methyltransferase (MGMT) promoter methylation in tumor tissue and any potential association with any observed anti-tumor effect.
• To evaluate the kinetics of the observed immunogenicity of glioblastoma multiform multi-antigen vaccine IMA950 plus GM-CSF.
• To explore the possible biomarker signatures that may predict immunological response to glioblastoma multiform multi-antigen vaccine IMA950 plus GM-CSF. (Exploratory)
• To explore the possible effects of this regimen on any observed pseudo-progression and pseudo-regression in these patients. (exploratory)

OUTLINE: This is a multicenter study. Patients are recruited to cohort 1 or 2 with priority recruitment to cohort 1. All patients undergo standard chemoradiotherapy followed by adjuvant temozolomide as planned.

• Standard therapy (chemoradiotherapy and adjuvant temozolomide): Beginning after surgery, patients receive chemoradiotherapy comprising oral temozolomide daily for 6 weeks and radiotherapy once daily, 5 days a week for 6 weeks. Beginning 35 days after completion of radiotherapy, patients receive adjuvant oral temozolomide alone on days 1-5. Treatment with temozolomide repeats every 28 days for 6 courses.

• Vaccine therapy: Patients also receive vaccine therapy beginning at one of two time points. Patients are recruited into 1 of 2 cohorts that differ in the timing of the vaccination schedule in relation to a patient's standard therapy.

  • Cohort 1: Vaccination begins 7-14 days prior to chemoradiotherapy.

    • Induction phase: Patients receive the first 6 doses of sargramostim intradermally (ID) followed by glioblastoma multiform multi-antigen vaccine IMA950 ID on days 1, 2, 3, 8, 15, and 22 in the absence of disease progression or unacceptable toxicity.
    • Maintenance phase: Patients receive sargramostim followed by glioblastoma multiform multi-antigen vaccine IMA950 ID on days 50 and 78 and then on day 21 of each adjuvant temozolomide course, beginning in course 1, for 3 courses in the absence of disease progression or unacceptable toxicity.

  • Cohort 2: Vaccination begins at least 7 days after chemoradiotherapy and 28 days prior to adjuvant temozolomide.

    • Induction phase: Patients receive the first 6 doses of sargramostim followed by glioblastoma multiform multi-antigen vaccine IMA950 ID as in cohort 1 induction phase, beginning at a different time point.
    • Maintenance phase: Patients receive sargramostim followed by glioblastoma multiform multi-antigen vaccine IMA950 ID on day 21 of each adjuvant temozolomide course, beginning in course 1, for 5 courses in the absence of disease progression or unacceptable toxicity.

Blood samples are collected periodically for pharmacodynamic, biomarker, and immunologic studies.

After completion of study treatment, patients are followed at 41 weeks.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 45 participants
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Cancer Research UK Phase I Trial of IMA950 (A Novel Multi-Peptide Vaccine) Plus GM-CSF in Patients With Newly Diagnosed Glioblastoma
• Study Start Date: July 2010
• Actual Primary Completion Date: February 2015
• Actual Study Completion Date: February 2015

Arms and Interventions

Outcome Measures

Primary Outcome Measures :

1. Causality of each adverse event (AE) to glioblastoma multiform multi-antigen vaccine IMA950 and GM-CSF and AE severity according to NCI CTCAE Version 4.0
2. Total number of patients showing patient-individual T-cell responses against a single or multiple tumor-associated peptides (TUMAP) contained in the study vaccine IMA950 at one or more post-vaccination time points by HLA multimer analysis

Secondary Outcome Measures :

1. Progression-free survival (PSF) at 6 and 9 months post-surgery as assessed by the Macdonald criteria from conventional gadolinium-enhanced MRI and clinical assessment
2. Correlation between steroid levels and observed T-cell responses
3. Correlation between O6-methyl-DNA-methyltransferase (MGMT) promoter methylation status in tumor tissue using methylation-specific polymerase chain reaction and clinical benefit (PFS at 6 months and 9 months)
4. Kinetics of vaccine-induced TUMAP responses including summary descriptions of the time of onset, sustainability, and magnitude of the observed response

Eligibility Criteria

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

Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed glioblastoma multiforme (astrocytoma WHO grade IV disease)

  • Newly diagnosed disease
  • Resectable tumor (not including patients undergoing biopsy only or tumors involving the brain stem or cerebellum)

• Meets 1 of the following criteria regarding standard chemoradiotherapy:

  • Cohort 1

    • Eligible for standard chemoradiotherapy with temozolomide followed by adjuvant temozolomide

      • Has undergone surgical resection before study enrollment

  • Cohort 2

    • Completed standard chemoradiotherapy with temozolomide with no subsequent progression of disease
• Expected to complete standard chemoradiotherapy and 6 courses of adjuvant temozolomide
• HLA-A*02 positive

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Life expectancy ≥ 30 weeks
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count ≥ 1.5 x 10^9/L
• Lymphocyte count ≥ 1.0 x 10^9/L (cohort 1) OR ≥ 0.35 x 10^9/L post-chemoradiotherapy and ≥ 1.0 x 10^9/L prior to the start of chemoradiotherapy (cohort 2)
• Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT or AST ≤ 3.0 times ULN
• Alkaline phosphatase ≤ 3.0 times ULN
• Hepatitis B serology negative (HBcAg-seronegative)
• No known hepatitis C or HIV serological positivity
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use one (male) or two (female) highly effective forms of contraception 2 weeks before, during, and for 6 months after completion of study therapy
• Not at high medical risk due to nonmalignant systemic disease including active uncontrolled infection
• No known hypersensitivity to GM-CSF or excipients
• No history of autoimmune disease
• No concurrent congestive heart failure
• No prior history of NYHA class III-IV cardiac disease, cardiac ischemia, or cardiac arrhythmia
• No other condition that might interfere with the patient's ability to generate an immune response
• No other condition that, in the investigator's opinion, would make the patient not a good candidate for the clinical trial

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 7 days since prior dexamethasone (dose > 4 mg daily or equivalent)
• At least 4 weeks since prior major surgery for any condition (except surgical resection as part of primary standard therapy in cohort 1)
• At least 30 days since prior and no concurrent participation in another clinical trial or planning to participate in another interventional clinical trial (concurrent participation on an observational study allowed)
• At least 30 days since prior and no other concurrent investigational drugs

• No prior treatment for glioblastoma including Gliadel Wafers

  • Early components of standard therapy are allowed if already initiated (i.e., surgical resection [cohort 1] or surgical resection followed by conventional external-beam radiotherapy and concomitant temozolomide [cohort 2])
• No other concurrent anticancer therapy
• No other concurrent vaccinations from 2 weeks before the first study vaccine to the end of the sixth study vaccine (the induction phase)

Contacts and Locations

Locations

United Kingdom

Addenbrooke's Hospital

Cambridge, England, United Kingdom, CB2 2QQ

UCL Cancer Institute

London, England, United Kingdom, WC1E 6DD

Southampton General Hospital

Southampton, England, United Kingdom, SO16 6YD

Beatson West of Scotland Cancer Centre

Glasgow, Scotland, United Kingdom, G12 0YN

Western General Hospital

Edinburgh, United Kingdom, EH4 2XU

St James' University Hospital

Leeds, United Kingdom, LS9 7TF

The Christie NHS Foundation Trust

Manchester, United Kingdom, M20 4BX

Sponsors and Collaborators

Cancer Research UK

Immatics Biotechnologies GmbH

Investigators

• Principal Investigator: Roy Rampling, MD, PhD; University of Glasgow

More Information

• Responsible Party: Cancer Research UK
• ClinicalTrials.gov Identifier: NCT01222221
• Other Study ID Numbers: CDR0000686559; CRUK-CR0902-11; EUDRACT-2009-015971-28
• First Posted: October 18, 2010
• Last Update Posted: October 14, 2015
• Last Verified: October 2015

Keywords provided by Cancer Research UK:

adult gliosarcoma; adult giant cell glioblastoma; adult glioblastoma

Additional relevant MeSH terms:

Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms by Site; Nervous System Diseases; Temozolomide; Sargramostim; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs