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

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.

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.

Eligibility Criteria:
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 per RECIST v1.1 criteria. In the case of retreatment, progression may be defined by the treating provider (e.g., clinical, radiographic, biochemical)
* Patients must have failed at least one prior systemic therapy (e.g. lanreotide, octreotide, everolimus, sunitinib, or lutetium Lu 177 dotatate)
* Patients who have been on somatostatin analogues (SSA) may continue to take SSA while on study treatment
* 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:

* Patients who have received temozolomide in the advanced disease setting either alone or as part of a combination therapy will be excluded
* 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
* Patients with Hepatitis B or Hepatitis C or HIV may be included if there are adequately controlled viral titers and no drug-drug interactions