Temozolomide and Survivin Long Peptide Vaccine (SurVaxM) for the Treatment of Patients With Progressing Metastatic Neuroendocrine Tumors

A Phase II Study of Temozolomide and Survivin Long Peptide Vaccine (SurVaxM) in Patients With Progressing Metastatic Neuroendocrine Tumors (NETs)

This phase II trial compares the safety and effect of temozolomide combined with survivin long peptide vaccine (SurVaxM) to temozolomide alone in patients with neuroendocrine tumors (NET) that has spread from where it first started (primary site) to other places in the body (metastatic) and is growing, spreading or getting worse (progressing). Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid and may kill tumor cells and slow down or stop tumor growth. Survivin, a protein, is expressed in 50% of patients that have neuroendocrine tumors and, is associated with poor outcomes. SVN53-67/M57-KLH peptide vaccine (SurVaxM) is a vaccine that has been shown to produce an immune system response against cancer cells that express a survivin and may block the growth of new tumor cells. Giving temozolomide with SurVaxM may kill more tumor cells in patients with progressing metastatic neuroendocrine tumors.

Study Overview

• Status: Not yet recruiting
• Conditions: Malignant Solid Neoplasm; Lung Neuroendocrine Neoplasm; Digestive System Neuroendocrine Neoplasm; Pancreatic Neuroendocrine Neoplasm
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Biological: Sargramostim; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Temozolomide; Biological: SVN53-67/M57-KLH Peptide Vaccine; Biological: Incomplete Freund''s Adjuvant

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the clinical efficacy (progression free survival [PFS]) of combining temozolomide and SVN53-67/M57-KLH peptide vaccine (SurVaxM) in patients with progressing NETs. (Part 1: Phase IIa Study) II. To evaluate the safety and toxicity of the study drug combination (temozolomide + SurVaxM) in patients with progressing NETs. (Part 1: Phase IIa Study) III. To evaluate the clinical efficacy (PFS) between patients treated with temozolomide alone compared to patients treated with the combination of SurVaxM + temozolomide. (Part 2: Phase IIb Study)

SECONDARY OBJECTIVES:

I. To assess clinical benefit (including complete response, partial response and stable disease as defined by Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1) at 3 months, 6 months, 9 months, and 12 months from study entry. (Part 1: Phase IIa Study) II. To assess anti-survivin IgG titer response. (Part 1: Phase IIa Study) III. Compare clinical benefit. (Part 2: Phase IIb Study) IV. Assess anti-survivin IgG titer response. (Part 2: Phase IIb Study) V. Assess safety. (Part 2: Phase IIb Study)

EXPLORATORY OBJECTIVES:

I. To explore immune markers associated with clinical responses to SurVaxM in peripheral blood of NETs patients. (Part 2: Phase IIb Study) II. To assess the methylguanine methyltransferase (MGMT) status of all patients and correlate with response. (Part 2: Phase IIb Study) III. To assess the tumor growth rate (TGR) on radiographic imaging prior to study enrollment and while on study. (Part 2: Phase IIb Study)

OUTLINE: Patients are assigned to 1 of 2 parts.

PART 1: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5. Treatment repeats every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity and can be continued at investigators discretion at end of treatment. Patients also receive SurVaxM with incomplete Freund's adjuvant (montanide ISA-51) subcutaneously (SC) and sargramostim SC once every 2 weeks for 4 doses. Patients with clinical benefit after 4 doses of SurVaxM and remain free of tumor progression and unacceptable toxicity may receive 3 additional doses on weeks 24, 36, and 48. Additionally, patients undergo blood sample collection, computed tomography (CT) scans or magnetic resonance imaging (MRI) scans throughout study.

PART 2: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days until disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT scans or MRI scans throughout study.

ARM II: Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days until disease progression or unacceptable toxicity and can be continued at investigators discretion at end of treatment. Patients also receive SurVaxM with montanide ISA-51 SC and sargramostim SC once every 2 weeks for 4 doses. Patients with clinical benefit after 4 doses of SurVaxM and remain free of tumor progression and unacceptable toxicity may receive 3 additional doses on weeks 24, 36, and 48. Additionally, patients undergo blood sample collection, CT scans or MRI scans throughout study.

After completion of study treatment, patients are followed up at 30 days.

• Study Type: Interventional
• Enrollment (Estimated): 132
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
      • Contact: Renuka V. Iyer; Phone Number: 716-845-8195; Email: Renuka.Iyer@RoswellPark.org
      • Principal Investigator: Renuka V. Iyer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years of age
• Have a Karnofsky performance status ≥ 80 or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 (i.e. the patient must be able to care for himself/ herself with occasional help from others)
• Measurable, pathologically confirmed diagnosis of neuroendocrine tumor of gastrointestinal, pancreatic, or lung origin
• Patients must have documented radiographic progression, determined as clinically significant by the treating provider, within the last twelve months on CT or MRI scans performed at least four weeks apart. In the case of retreatment, progression may be defined by the treating provider (e.g., clinical, radiographic, biochemical)
• Archival neuroendocrine tumor tissue must test positive for survivin presence by clinical immunohistochemistry prior to study enrollment
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (obtained within 14 days prior to enrollment)
• Platelets ≥ 100 x 10^9/L (obtained within 14 days prior to enrollment)
• Hemoglobin (Hgb) > 9g/dL (obtained within 14 days prior to enrollment)
• Plasma total bilirubin: ≤ 1.5 x upper limit of normal (ULN) (obtained within 14 days prior to enrollment)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 4 x ULN (obtained within 14 days prior to enrollment)
• Creatinine clearance ≥ 60 mL/min (per Cockroft-Gault equation) (obtained within 14 days prior to enrollment)

• Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW] heparin) must meet the following criteria:

  • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices, which carries a significant risk of bleeding in investigator's opinion)
• Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Participant must understand the investigational nature of this study and sign an independent ethics committee/institutional review board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

• Has received prior treatment with SurVaxM
• Received an investigational agent within 30 days prior to enrollment
• Participants who have received checkpoint inhibitors within 3 months prior to study enrollment or, those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, bradycardia, tachycardia or psychiatric illness/social situations that would limit compliance with study requirements and, which in the treating physicians' opinion would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety
• Patients with a concurrent or prior malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Patients who have been free of disease (any prior malignancy) for at least 3 years are eligible for this study
• Known history of an autoimmune disorder
• Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS) related illness or other serious medical illness
• Systemic corticosteroid therapy > 2mg of dexamethasone or equivalent per day at study entry
• Pregnant or nursing female participants
• Unwilling or unable to follow protocol requirements
• Any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ARM I (temozolomide); Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days until disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT scans or MRI scans throughout study.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; TMZ; CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Gliotem; Temizole
Experimental: ARM II (temozolomide, SurVaxM); Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days until disease progression or unacceptable toxicity and can be continued at investigators discretion at end of treatment. Patients also receive SurVaxM with Montanide ISA-51 SC and sargramostim SC once every 2 weeks for 4 doses. Patients with clinical benefit after 4 doses of SurVaxM and remain free of tumor progression and unacceptable toxicity may receive 3 additional doses on weeks 24, 36, and 48. Additionally, patients undergo blood sample collection, CT scans or MRI scans throughout study.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Biological: Sargramostim; Given SC; Other Names: 23-L-Leucinecolony-Stimulating Factor 2; DRG-0012; Leukine; Prokine; rhu GM-CFS; Sagramostim; Sargramostatin; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; TMZ; CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Gliotem; Temizole; Biological: SVN53-67/M57-KLH Peptide Vaccine; Given SC; Other Names: SurVaxM; Biological: Incomplete Freund''s Adjuvant; Given SC; Other Names: IFA; ISA-51; Montanide ISA 51; Freund's Incomplete Adjuvant; Montanide ISA-51; incomplete Freund's adjuvant
Experimental: PART 1 (temozolomide, SurVaxM); Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity and can be continued at investigators discretion at end of treatment. Patients also receive SurVaxM with montanide ISA-51 SC and sargramostim SC once every 2 weeks for 4 doses. Patients with clinical benefit after 4 doses of SurVaxM and remain free of tumor progression and unacceptable toxicity may receive 3 additional doses on weeks 24, 36, and 48. Additionally, patients undergo blood sample collection, CT scans or MRI scans throughout study.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Biological: Sargramostim; Given SC; Other Names: 23-L-Leucinecolony-Stimulating Factor 2; DRG-0012; Leukine; Prokine; rhu GM-CFS; Sagramostim; Sargramostatin; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; TMZ; CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Gliotem; Temizole; Biological: SVN53-67/M57-KLH Peptide Vaccine; Given SC; Other Names: SurVaxM; Biological: Incomplete Freund''s Adjuvant; Given SC; Other Names: IFA; ISA-51; Montanide ISA 51; Freund's Incomplete Adjuvant; Montanide ISA-51; incomplete Freund's adjuvant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS) (Part 1)	Summarized using frequencies and relative frequencies.	At 6 months
Incidence of adverse events (Part 1)	Defined using National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAE) version (v) 5.0. Adverse events will be summarized by attribution and grade using frequencies and relative frequencies.	Up to 1 year
PFS (Part 2)	Clinical benefit compared between treatment arms. PFS will be summarized by study arm using frequencies and relative frequencies.	At 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response (Part 1)	Assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Response will be summarized by time-point using frequencies and relative frequencies. Clinical benefit (best response of complete response [CR], partial response [PR] or stable disease [SD]) will be estimated and summarized using frequencies and relative frequencies, with a 95% confidence interval obtained for the clinical benefit rate.	At 3, 6, 9 and 12 months from study entry
Overall survival (OS) (Part 1)	OS will be summarized using standard Kaplan-Meier methods, where the median will be estimated with a 95% confidence interval.	At the time from treatment initiation until death due to any cause up to 1 year
Time to progression (TTP) (Part 1)	Defined using RECIST v1.1. TTP will be summarized using standard Kaplan-Meier methods, where the median will be estimated with a 95% confidence interval.	At the time from treatment initiation until disease progression, death or last follow up up to 1 year
Titer response (Part 1)	Defined as anti-survivin IgG titers > 30,000 and will be summarized using frequencies and relative frequencies.	Up to 1 year
Response (Part 2)	Assessed using RECIST v1.1. Response will be summarized by study arm and timepoint using frequencies and relative frequencies. Clinical benefit (best response of CR, PR, or SD) will be estimated and summarized by study arm using frequencies and relative frequencies, with a 95% confidence interval obtained for the clinical benefit rate.	At 6, 9, and 12 months from study entry
OS (Part 2)	OS will be summarized by study arm using standard Kaplan-Meier methods, where the median will be estimated with a 95% confidence interval.	At time from treatment initiation until death due to any cause up to 1 year
TTP (Part 2)	Assessed using RECIST v1.1. TTP will be summarized by study arm using standard Kaplan-Meier methods, where the median will be estimated with a 95% confidence interval.	At time from treatment initiation until disease progression, death or last follow-up up to 1 year
Titer response (Part 2)	Defined as anti-survivin IgG titers > 30,000 and will be summarized by study arm using frequencies and relative frequencies.	Up to 1 year
Incidence of adverse events (Part 2)	Adverse events are defined using NCI CTCAE v5.0 and will be summarized by attribution, study arm, and grade using frequencies and relative frequencies.	Up to 1 year

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Investigators: Principal Investigator: Renuka V Iyer, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start (Estimated): April 15, 2024
• Primary Completion (Estimated): January 15, 2027
• Study Completion (Estimated): January 15, 2028

Study Registration Dates

• First Submitted: December 29, 2023
• First Submitted That Met QC Criteria: December 29, 2023
• First Posted (Actual): January 11, 2024

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplasms; Neuroendocrine Tumors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Adjuvants, Immunologic; Temozolomide; Sargramostim; Monatide (IMS 3015); Freund's Adjuvant
• Other Study ID Numbers: I 3622923 (Other Identifier: Roswell Park Cancer Institute); NCI-2023-09345 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes