HeatShock: HSPPC-96 Vaccine With Temozolomide in Patients With Newly Diagnosed GBM

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00905060
• Collaborator: Agenus Inc. (Industry)
• Enrollment: 70
• Locations: 9
• Arm: 1
• Actual Duration (Months): 59.1
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects and how well HSPPC-96 (vitespen) and temozolomide work in treating patients with newly diagnosed glioblastoma multiforme. Vaccines made from a person's tumor cells and heat shock protein peptide may help the body to 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, by stopping them from dividing, or by stopping them from spreading. Giving HSPPC-96 (vitespen) together with temozolomide may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Biological: HSPPC-96; Drug: Temozolomide; Procedure: Standard Surgical Resection	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the safety profile of HSPPC-96 (vitespen) administered concurrently with temozolomide in patients with newly diagnosed glioblastoma multiforme (GBM).

2. To evaluate survival in patients treated with an autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) with concurrent temozolomide.

SECONDARY OBJECTIVES:

1. To evaluate progression-free survival (PFS) from date of surgical resection. II. To evaluate the immunologic response to vaccine treatment in a subset of evaluable patients.

OUTLINE:

Approximately 2-5 weeks after standard radiation therapy and temozolomide completion, patients receive vitespen intradermally (ID) on days 1, 8, 15, and 22. Beginning 2 weeks after the 4th dose of vitespen, patients receive a 5th dose of vitespen ID and maintenance temozolomide orally (PO) on days 1-5 (of 28 day courses). On day 21 of course 1, patients receive the 6th dose of vitespen ID and continue vaccinations monthly. Courses repeat every 28 days in the absence of vaccine depletion, disease progression, or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: PHASE 2, Multi-center, Single Arm Investigation of HSPPC-96 Vaccine With Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme
• Actual Study Start Date: Jun 29, 2009
• Actual Primary Completion Date: Jun 3, 2014
• Actual Study Completion Date: Jun 3, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Protein Peptide-Complex (HSPPC-96) Patients will receive 4 weekly injections of HSPPC-96 followed by a 5th vaccine injection on the same day of the start of maintenance temozolomide administered 2 weeks (+ 4 days) following vaccine administration #4 on the same day of the start of maintenance temozolomide (Day 36). Monthly vaccine injections will then begin on day 21 (+/- 7 days) of the first 28 day temozolomide cycle (Day 56 of the study), 3 weeks following vaccine administration #5 and will continue every 28 days until depletion of vaccine or progression.

Biological: HSPPC-96; Autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) administered at 25 μg per dose injected intradermally once weekly for 4 consecutive weeks and monthly following standard treatment with radiation and temozolomide.; Other Names: Heat Shock Vitespen ; Drug: Temozolomide; Maintenance temozolomide treatment is given 2 weeks after administration of the fourth vaccine at an initial dose of 150 mg per square meter (mg/m2) for 5 consecutive days in a 28-day cycle. The dose was increased to 200 mg/m2 for 5 days in subsequent cycles.; Other Names: Temodar ; Procedure: Standard Surgical Resection; Patients will undergo standard surgical resection of intracranial tumor; Other Names: Craniotomy

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-Related Adverse Events of Any Grade [Up to 3 years]

2. Median Overall Survival [Up to 3 years]

   Overall survival is defined as the time from surgical resection to death of any cause.

Secondary Outcome Measures

1. Median Progression Free Survival (PFS) [Up to 3 years]

   PFS is defined as the duration of progression-free survival from the time from resection until either documented disease progression or death

2. Median PD-L1 Positivity in Circulating Myeloid Cells [Up to 53 Weeks]

   Circulating myeloid cells (CD45+/CD11b+) obtained from patients at the time of surgery were analyzed for PD-L1 expression to determine the percent of myeloid cells positive for PD-L1 (cut off for positivity determined relative to Fluorescence Minus One (FMO) and isotype control).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Pre-surgery tissue acquisition Inclusion criteria

1. Age > or equal to 18 years old

2. Life expectancy of greater than 12 weeks.

3. Able to read and understand the informed consent document; must sign the informed consent

4. Must have suspected diagnosis of Glioblastoma Multiforme with a surgical intent to resect at least 90% of enhancing disease

5. Must be eligible for post-surgical treatment with radiotherapy and temozolomide

Post-radiation therapy/pre-vaccine eligibility Inclusion criteria

1. Agree to use contraception or abstain from sexual activity from the time of consent through 1 month after the end of study drug administration

2. Negative serum pregnancy test for female patients of childbearing potential

3. Patients with histologically proven, non-progressive glioblastoma multiforme (GBM)

4. Patient must have received standard of care radiation and temozolomide therapy

5. Must have undergone a at least a 90% resection (determined by the principal investigator (PI)) measured by postoperative magnetic resonance imaging (MRI) scan, T1-weighted contrast scan, or CT scan if clinically indicated, performed within 72 hours after surgery

6. All radiotherapy must be discontinued at least 2 weeks and no more than 5 weeks prior to the first planned vaccine administration

7. Availability of at least 4 doses of vaccine (at least 4 vials for clinical administration produced from the tumor provided)

8. Karnofsky functional status rating > or equal to 70

9. Adequate bone marrow function including the absence of lymphopenia (ANC > 1,500/ mm3; absolute lymphocyte count (ALC) > 500/mm3 ; platelet count >100,000/mm3), adequate liver function (serum glutamic oxaloacetic transaminase/ aspartate aminotransferase (AST), alanine amino transferase (ALT), and alkaline phosphatase <2.5 times institutional upper limit of normals [IULNs] and bilirubin (total) <1.5 mg*IULN), and adequate renal function (BUN and creatinine <1.5 times IULNs

Exclusion Criteria:

Pre-surgery tissue acquisition

1. Current diagnosis of Human Immunodeficiency Virus (HIV testing is not required per protocol)

2. Any prior diagnosis of any other cancer or other concurrent malignancy, with the exception of adequately treated nonmetastatic in situ carcinoma of the uterine cervix or nonmetastatic nonmelanoma skin cancer unless in complete remission and off all therapy for that disease for a minimum of 5 years

3. Any systemic autoimmune disease (e.g., Hashimoto's thyroiditis) and/or any history of primary or secondary immunodeficiency

4. Any prior therapy for glioma

5. Planned use or current use of other investigational therapy for the treatment of glioma

Post-radiation therapy/pre-vaccine Exclusion

1. Inability to comply with study-related procedures

2. Prior diagnosis of any other cancer or other concurrent malignancy, with the exception of adequately treated nonmetastatic in situ carcinoma of the uterine cervix or nonmetastatic nonmelanoma skin cancer unless in complete remission and off all therapy for that disease for a minimum of 5 years

3. Current or active use of chemotherapy (except temozolomide) or immune therapy

4. Contrast MRI findings (or CT scan if MRI is clinically contraindicated) consistent with progression per protocol defined modified Response assessment in neuro-oncology criteria (RANO) criteria. Progression prior to vaccination as determined by the Principal Investigator

5. Patients with active uncontrolled infection

6. Evidence of bleeding diathesis

7. Unstable or severe intercurrent medical conditions

8. Female patients who are pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94115
2	University of Miami	Miami	Florida	United States	33136
3	Northwestern University	Chicago	Illinois	United States	60611
4	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
5	The Valley Hospital	Paramus	New Jersey	United States	07652
6	Northern Westchester Hospital	Mount Kisco	New York	United States	10549
7	Columbia University	New York	New York	United States	10032
8	University of Oklahoma	Oklahoma City	Oklahoma	United States	73104
9	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of California, San Francisco
• Agenus Inc.

Investigators

• Principal Investigator: Jennifer Clarke, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Orin Bloch, MD, Principal Investigator, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00905060
• Other Study ID Numbers: 081010; C-100-37; NCI-2015-01229; NCT00912951
• First Posted: May 20, 2009
• Last Update Posted: Mar 24, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Orin Bloch, MD, Principal Investigator, University of California, San Francisco: Newly Diagnosed Glioblastoma Multiforme, vaccine
• Additional relevant MeSH terms: Nervous System Neoplasms; Central Nervous System Neoplasms; Temozolomide

Study Results

Participant Flow

Recruitment Details	Recruitment took place between June 29, 2009 and April 2012 for participants scheduled for gross total resection of recurrent Glioblastoma multiforme (GBM) across 8 sites

Arm/Group Title	Protein Peptide-Complex (HSPPC-96)
Arm/Group Description	Patients will receive 4 weekly injections of HSPPC-96 followed by a 5th vaccine injection on the same day of the start of maintenance temozolomide administered 2 weeks (+ 4 days) following vaccine administration #4 on the same day of the start of maintenance temozolomide (Day 36). Monthly vaccine injections will then begin on day 21 (+/- 7 days) of the first 28 day temozolomide cycle (Day 56 of the study), 3 weeks following vaccine administration #5 and will continue every 28 days until depletion of vaccine or progression. HSPPC-96: Autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) administered at 25 μg per dose injected intradermally once weekly for 4 consecutive weeks and monthly following standard treatment with radiation and temozolomide.
Period Title: Surgical Resection
STARTED	70
COMPLETED	46
NOT COMPLETED	24
Period Title: Surgical Resection
STARTED	46
COMPLETED	46
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Protein Peptide-Complex (HSPPC-96)
Arm/Group Description	Patients will receive 4 weekly injections of HSPPC-96 followed by a 5th vaccine injection on the same day of the start of maintenance temozolomide administered 2 weeks (+ 4 days) following vaccine administration #4 on the same day of the start of maintenance temozolomide (Day 36). Monthly vaccine injections will then begin on day 21 (+/- 7 days) of the first 28 day temozolomide cycle (Day 56 of the study), 3 weeks following vaccine administration #5 and will continue every 28 days until depletion of vaccine or progression. HSPPC-96: Autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) administered at 25 μg per dose injected intradermally once weekly for 4 consecutive weeks and monthly following standard treatment with radiation and temozolomide.
Overall Participants	70
Age, Customized (Count of Participants)
30-39 years old	2 2.9%
40-49 years old	13 18.6%
50-59 years old	19 27.1%
60-69 years old	25 35.7%
70-79 years old	11 15.7%
Sex: Female, Male (Count of Participants)
Female	32 45.7%
Male	38 54.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2.9%
Not Hispanic or Latino	67 95.7%
Unknown or Not Reported	1 1.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 4.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 1.4%
White	65 92.9%
More than one race	1 1.4%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	70 100%
Median Number of Vaccination Doses Administered (vaccine injections) [Median (Full Range) ]
Median (Full Range) [vaccine injections]	9

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-Related Adverse Events of Any Grade
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Protein Peptide-Complex (HSPPC-96)
Arm/Group Description	Patients will receive 4 weekly injections of HSPPC-96 followed by a 5th vaccine injection on the same day of the start of maintenance temozolomide administered 2 weeks (+ 4 days) following vaccine administration #4 on the same day of the start of maintenance temozolomide (Day 36). Monthly vaccine injections will then begin on day 21 (+/- 7 days) of the first 28 day temozolomide cycle (Day 56 of the study), 3 weeks following vaccine administration #5 and will continue every 28 days until depletion of vaccine or progression. HSPPC-96: Autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) administered at 25 μg per dose injected intradermally once weekly for 4 consecutive weeks and monthly following standard treatment with radiation and temozolomide.
Measure Participants	46
Count of Participants [Participants]	34 48.6%

2. Primary Outcome

Title	Median Overall Survival
Description	Overall survival is defined as the time from surgical resection to death of any cause.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Protein Peptide-Complex (HSPPC-96)
Arm/Group Description	Patients will receive 4 weekly injections of HSPPC-96 followed by a 5th vaccine injection on the same day of the start of maintenance temozolomide administered 2 weeks (+ 4 days) following vaccine administration #4 on the same day of the start of maintenance temozolomide (Day 36). Monthly vaccine injections will then begin on day 21 (+/- 7 days) of the first 28 day temozolomide cycle (Day 56 of the study), 3 weeks following vaccine administration #5 and will continue every 28 days until depletion of vaccine or progression. HSPPC-96: Autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) administered at 25 μg per dose injected intradermally once weekly for 4 consecutive weeks and monthly following standard treatment with radiation and temozolomide.
Measure Participants	46
Median (95% Confidence Interval) [months]	23.8

3. Secondary Outcome

Title	Median Progression Free Survival (PFS)
Description	PFS is defined as the duration of progression-free survival from the time from resection until either documented disease progression or death
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Protein Peptide-Complex (HSPPC-96)
Arm/Group Description	Patients will receive 4 weekly injections of HSPPC-96 followed by a 5th vaccine injection on the same day of the start of maintenance temozolomide administered 2 weeks (+ 4 days) following vaccine administration #4 on the same day of the start of maintenance temozolomide (Day 36). Monthly vaccine injections will then begin on day 21 (+/- 7 days) of the first 28 day temozolomide cycle (Day 56 of the study), 3 weeks following vaccine administration #5 and will continue every 28 days until depletion of vaccine or progression. HSPPC-96: Autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) administered at 25 μg per dose injected intradermally once weekly for 4 consecutive weeks and monthly following standard treatment with radiation and temozolomide.
Measure Participants	46
Median (95% Confidence Interval) [months]	18

4. Secondary Outcome

Title	Median PD-L1 Positivity in Circulating Myeloid Cells
Description	Circulating myeloid cells (CD45+/CD11b+) obtained from patients at the time of surgery were analyzed for PD-L1 expression to determine the percent of myeloid cells positive for PD-L1 (cut off for positivity determined relative to Fluorescence Minus One (FMO) and isotype control).
Time Frame	Up to 53 Weeks

Outcome Measure Data

Analysis Population Description

Peripheral blood was available for analysis from 32 vaccine-treated patients

Arm/Group Title	Protein Peptide-Complex (HSPPC-96)
Arm/Group Description	Patients will receive 4 weekly injections of HSPPC-96 followed by a 5th vaccine injection on the same day of the start of maintenance temozolomide administered 2 weeks (+ 4 days) following vaccine administration #4 on the same day of the start of maintenance temozolomide (Day 36). Monthly vaccine injections will then begin on day 21 (+/- 7 days) of the first 28 day temozolomide cycle (Day 56 of the study), 3 weeks following vaccine administration #5 and will continue every 28 days until depletion of vaccine or progression. HSPPC-96: Autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) administered at 25 μg per dose injected intradermally once weekly for 4 consecutive weeks and monthly following standard treatment with radiation and temozolomide.
Measure Participants	32
Median (95% Confidence Interval) [percentage of PD-L1 positivity]	54.5

Adverse Events

Time Frame	Up to 3 years
Adverse Event Reporting Description	Adverse events were reported for the participants who received at least one injection of the vaccine or one dose of temozolomide (TMZ)
Arm/Group Title	Protein Peptide-Complex (HSPPC-96)
Arm/Group Description	Patients will receive 4 weekly injections of HSPPC-96 followed by a 5th vaccine injection on the same day of the start of maintenance temozolomide administered 2 weeks (+ 4 days) following vaccine administration #4 on the same day of the start of maintenance temozolomide (Day 36). Monthly vaccine injections will then begin on day 21 (+/- 7 days) of the first 28 day temozolomide cycle (Day 56 of the study), 3 weeks following vaccine administration #5 and will continue every 28 days until depletion of vaccine or progression. HSPPC-96: Autologous tumor-derived heat shock protein peptide-complex (HSPPC-96) administered at 25 μg per dose injected intradermally once weekly for 4 consecutive weeks and monthly following standard treatment with radiation and temozolomide.
All Cause Mortality
	Protein Peptide-Complex (HSPPC-96)
	Affected / at Risk (%)	# Events
Total	21/46 (45.7%)
Serious Adverse Events
	Protein Peptide-Complex (HSPPC-96)
	Affected / at Risk (%)	# Events
Total	10/46 (21.7%)
Blood and lymphatic system disorders
Thromboembolic event	1/46 (2.2%)
General disorders
Pain	1/46 (2.2%)
Infections and infestations
Infections and infestations - Other	1/46 (2.2%)
Musculoskeletal and connective tissue disorders
Muscle weakness left-sided	1/46 (2.2%)
Nervous system disorders
Seizure	3/46 (6.5%)
Syncope	1/46 (2.2%)
Cognitive disturbance	1/46 (2.2%)
Hydrocephalus	1/46 (2.2%)
Other (Not Including Serious) Adverse Events
	Protein Peptide-Complex (HSPPC-96)
	Affected / at Risk (%)	# Events
Total	44/46 (95.7%)
Blood and lymphatic system disorders
Anemia	6/46 (13%)	21
Cardiac disorders
Acute coronary syndrome	1/46 (2.2%)	1
Ear and labyrinth disorders
Hearing impaired	1/46 (2.2%)	1
Eye disorders
Blurred vision	1/46 (2.2%)	1
Gastrointestinal disorders
Constipation	3/46 (6.5%)	3
Nausea	3/46 (6.5%)	6
Oral hemorrhage	2/46 (4.3%)	2
Vomiting	2/46 (4.3%)	4
Dental caries	1/46 (2.2%)	1
Diarrhea	1/46 (2.2%)	1
Dyspepsia	1/46 (2.2%)	1
Mucositis oral	1/46 (2.2%)	2
General disorders
Fatigue	6/46 (13%)	14
Injection site reaction	16/46 (34.8%)	16
Pain	2/46 (4.3%)	3
Chills	1/46 (2.2%)	1
Edema limbs	1/46 (2.2%)	1
Fever	1/46 (2.2%)	3
Gait disturbance	1/46 (2.2%)	1
Immune system disorders
Allergic reaction	1/46 (2.2%)	1
Infections and infestations
Abdominal infection	1/46 (2.2%)	1
Upper respiratory infection	1/46 (2.2%)	1
Urinary tract infection	1/46 (2.2%)	1
Investigations
Lymphocyte count decreased	7/46 (15.2%)	28
White blood cell decreased	4/46 (8.7%)	19
Platelet count decreased	3/46 (6.5%)	11
Alanine aminotransferase increased	2/46 (4.3%)	3
Alkaline phosphatase increased	1/46 (2.2%)	2
Aspartate aminotransferase increased	1/46 (2.2%)	1
Blood bilirubin increased	1/46 (2.2%)	1
CPK increased	1/46 (2.2%)	1
Neutrophil count decreased	1/46 (2.2%)	1
Metabolism and nutrition disorders
Hyperglycemia	7/46 (15.2%)	11
Anorexia	2/46 (4.3%)	2
Hypokalemia	2/46 (4.3%)	3
Hypernatremia	1/46 (2.2%)	1
Hypoalbuminemia	1/46 (2.2%)	1
Hypocalcemia	1/46 (2.2%)	1
Hypoglycemia	1/46 (2.2%)	1
Hyponatremia	1/46 (2.2%)	3
Musculoskeletal and connective tissue disorders
Neck pain	2/46 (4.3%)	2
Arthralgia	1/46 (2.2%)	1
Back pain	1/46 (2.2%)	1
Chest wall pain	1/46 (2.2%)	1
Pain in extremity	1/46 (2.2%)	1
Myalgia	1/46 (2.2%)	1
Nervous system disorders
Seizure	6/46 (13%)	7
Ataxia	4/46 (8.7%)	5
Peripheral motor neuropathy	4/46 (8.7%)	6
Headache	3/46 (6.5%)	5
Memory Impairment	3/46 (6.5%)	4
Nervous system disorders - Other	3/46 (6.5%)	4
Dysphasia	2/46 (4.3%)	2
Depressed level of consciousness	1/46 (2.2%)	1
Dizziness	1/46 (2.2%)	1
Facial nerve disorder	1/46 (2.2%)	1
Peripheral sensory neuropathy	1/46 (2.2%)	2
Pyramidal tract syndrome	1/46 (2.2%)	1
Tremor	1/46 (2.2%)	1
Psychiatric disorders
Depression	2/46 (4.3%)	2
Anxiety	1/46 (2.2%)	1
Insomnia	1/46 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/46 (2.2%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/46 (2.2%)	1
Pruritus	2/46 (4.3%)	2
Rash maculo-papular	1/46 (2.2%)	1
Urticaria	1/46 (2.2%)	1
Erythema	3/46 (6.5%)	3
Vascular disorders
Flushing	1/46 (2.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.