Cvac as Maintenance Treatment in Patients With Epithelial Ovarian Cancer in Complete Remission Following First-line Chemotherapy or Second-line Treatment

As \< 10% of the necessary patients required by the protocol were recruited and the data were not intended to support a labeling claim, it was determined that the abbreviated clinical study report (CSR) was the appropriate reporting format. No efficacy analyses were performed as the trial was terminated early with incomplete enrollment of \< 10%.

The purpose of this study is to determine if an investigational cell therapy called Cvac can help epithelial ovarian cancer (EOC) from returning when administered to patients who are in complete remission after surgical removal of their tumor followed by standard first-line (Part A) or second-line (Part B) chemotherapy. Following remission, patients will undergo leukapheresis for the manufacture of the study agent. After completion of chemotherapy and confirmation of remission, patients will enter the treatment phase of the study.

This study proposes a nontoxic immunotherapeutic approach to extend overall survival in patients in complete remission. Most patients with ovarian cancer achieve complete clinical remission after optimal debulking surgery and first-line platinum-based chemotherapy. However, most patients, despite high response rates to first-line treatment, will relapse and undergo subsequent chemotherapy. Generally, the progression-free interval between treatments becomes shorter with each relapse, and the patient eventually dies of the disease.

For production of Cvac, each patient's cells were enriched using cell separation techniques. The patient's cells were cultured for 5 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) in AIM V® serum-free tissue culture medium (Thermo Fisher Scientific) to cultivate the growth of dendritic cells (DC). The culture was pulsed overnight with the antigen (mannosylated mucin 1 fusion protein \[M-FP\]) to arm the DCs to the specific mucin 1 antigen. After harvesting, the M-FP-pulsed DCs were formulated as a finished product (Cvac) in 1 mL aliquots, diluted in 5% human serum albumin (HSA) and 10% dimethyl sulfoxide (DMSO) at an approximate concentration of 60 × 10\^6 viable DCs/mL. The vials were cryopreserved and stored in the vapor phase of liquid nitrogen at the manufacturing facility.

Different participants were enrolled in the 2 parts of the study.

Part A

To be eligible for participation, patients were diagnosed with stage III or IV epithelial ovarian cancer, underwent optimal debulking surgery (≤ 1 cm of residual disease), underwent platinum and taxane chemotherapy, with or without bevacizumab, and had a tumor that overexpressed mucin 1, as well as met all other study inclusion and exclusion criteria at screening.

Patients who met all study inclusion and exclusion criteria were randomized in a 1:1 double-blinded fashion to either the Cvac (active) group or the placebo (control) group. After randomization, patients underwent mononuclear cell (MNC) collection for production of the study agent and then began first-line chemotherapy. After completion of chemotherapy and confirmation of complete clinical and radiological remission (Baseline), patients were entered into the treatment phase of the study.

A total of 76 patients were recruited and randomized at centers in Europe, North America, and Australia.

Part B

To be eligible for participation, patients had first-line platinum-based chemotherapy with a complete response lasting for at least 6 months prior to relapse and achieved second remission following standard platinum-based second-line chemotherapy with or without a second bulk-reducing surgery, and had a tumor that over-expressed mucin 1, as well as met all other study inclusion and exclusion criteria.

Patients who met all study inclusion and exclusion criteria were randomized in a 1:1 fashion to either the Cvac (active) group or the observational standard of care (control) group. After randomization, only patients randomized to Cvac underwent MNC collection for production of the study agent. After confirmation of no evidence of disease at the Baseline visit, patients were entered into the treatment phase of the study.

A total of 15 patients were recruited and randomized at centers in Europe.

Eligibility Criteria:
Part A: First Remission

Inclusion Criteria (Part A):

1. Females ≥ 18 years of age at screening with a confirmed diagnosis of Stage III or IV epithelial ovarian, primary peritoneal, or fallopian tube cancer.
2. Undergone optimal debulking surgery, defined as ≤ 1 cm of residual tumor.
3. Undergone standard platinum and taxane first-line chemotherapy.
4. Signed an informed consent form (ICF).
5. Completed study procedures within the study timelines.
6. Mucin 1-positive tumor as determined by central immunohistopathology.
7. Adequate renal function in the opinion of the investigator based on serum creatinine and/or glomerular filtration rate.
8. Adequate liver function, defined as serum glutamic oxaloacetic transaminase/aspartate aminotransferase (SGOT/AST) and serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) ≤ 2× ULN and serum bilirubin ≤ 1.5 × ULN, unless Gilbert's syndrome had been previously confirmed for the patient.
9. Adequate bone marrow function, defined as white blood cells (WBCs) ≥ 3.0 K/µL, absolute neutrophil count (ANC) ≥ 1.5 × 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 × 109/L.
10. Life expectancy of at least 12 months at the time of screening as judged by the investigator.
11. Not pregnant, and if of childbearing potential, agreed to use a highly effective method of birth control (implanted, injectable, or oral combination hormonal method alone or in possible combinations, intrauterine device, vasectomized partner, or abstinence) prior to study entry, for the duration of the study, and for 3 months after the last dose of study agent. Male partners of a study patient must use a condom in addition to the acceptable method of contraception for the female partner, as specified above.

Exclusion Criteria (Part A):

1. Non-epithelial ovarian cancer, including ovarian germ cell, sarcoma, mixed Müllerian tumors, or mucinous carcinoma of the peritoneum.
2. Malignancy other than epithelial ovarian cancer, except those that had been in complete response for a minimum of 3 years, and except carcinoma in-situ of the cervix or basal cell and squamous cell carcinomas of the skin that had been adequately treated.
3. Treatment with any investigational product (for any condition) within 4 weeks of screening.
4. Concurrent systemic treatment with steroids or other immunosuppressant agents at a dose considered by the investigator to be higher than a standard physiological dose.
5. Evidence of severe or uncontrolled cardiac disease, including myocardial infarction or unstable angina within 6 months of screening, congestive heart failure, or ventricular arrhythmias requiring medication.
6. Clinically significant abnormalities as measured by electrocardiogram (ECG).
7. Active uncontrolled infection.
8. Uncontrolled hypertension.
9. Diagnosed immunodeficiency or autoimmune disorder.
10. Infection with human immunodeficiency virus (HIV) or hepatitis C virus (HCV), or active and infectious hepatitis B virus (HBV) infection.
11. Pregnant or lactating.
12. Evidence or history of central nervous system metastasis.
13. Known hypersensitivity to any of the components of the study agent.
14. Active or latent infection with Mycobacterium tuberculosis in any body tissue (especially renal and/or lung).
15. Any other health condition that would preclude participation in the study in the judgment of the principal investigator.

Part B: Second Remission

Inclusion Criteria (Part B):

1. Females ≥ 18 years of age at screening with a confirmed diagnosis of epithelial ovarian, fallopian tube, or peritoneal cancer.
2. Underwent standard cytoreductive surgery and first-line chemotherapy containing platinum before first relapse and were in complete remission for at least 6 months prior to relapse.
3. Relapsed once and then underwent standard platinum-based second-line chemotherapy (at least 3 cycles is required) with or without a second bulk-reducing surgery.
4. Second remission defined as:

   1. No definitive evidence of disease (NED) on computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis;
   2. CA-125 ≤ upper limit of normal (ULN) or 90% reduction in CA-125 since start of second-line chemotherapy;
   3. Negative physical exam (ie, no clinical signs).
5. Life expectancy ≥ 3 months in the opinion of the investigator.
6. Signed an informed consent form (ICF).
7. Willing and able to complete study procedures within the expected study timelines.
8. Mucin 1-positive tumor as determined by central immunohistopathology.
9. Histologically documented EOC, fallopian tube, or peritoneal cancer (patients with pseudomyxoma, mesothelioma, unknown primary tumor, sarcoma, or neuroendocrine histology, with borderline ovarian cancer, ie, patients with low malignant potential tumors, and with clear cell or mucinous histology are excluded).
10. Adequate end-organ and hematological function as defined by:

    1. Adequate bone marrow function: white blood cells (WBCs) ≥ 3.0 K/µL, absolute neutrophil count (ANC) ≥ 1.5 × 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 × 109/L.
    2. Adequate renal function, defined as serum creatinine ≤ 1.5 × ULN.
    3. Adequate liver function, defined as serum glutamic oxaloacetic transaminase/aspartate aminotransferase (SGOT/AST) and serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) ≤ 2 × ULN and serum bilirubin ≤ 1.5 × ULN.
11. Generally well-controlled blood pressure with systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg prior to randomization (antihypertensive medications are permitted). Low-dose chronic hormonal or steroidal treatments are also permitted.
12. Not pregnant, and if of childbearing potential, agrees to use a highly effective method of birth control (implanted, injectable, or oral combination hormonal method alone or in possible combinations, intrauterine device, vasectomized partner, or abstinence) prior to study entry, for the duration of the study, and for 3 months after the last dose of study agent. Male partners of a study patient must use a condom in addition to the acceptable method of contraception for the female partner, as specified above.
13. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 (applicable at the baseline visit only).

Exclusion Criteria (Part B):

1. More than 2 previous lines of chemotherapy for EOC, fallopian tube, or peritoneal cancer.
2. Primary platinum-refractory or platinum-resistant disease (ie, patients who progress prior to cessation of induction therapy \[platinum refractory\] or recur within 6 months after cessation \[platinum resistant\]).
3. Treatment with any investigational product (for any condition) within 4 weeks of screening. Enrolled in or has not completed at least 28 days of treatment (prior to screening) since ending another investigational device or drug treatment, or currently receiving other investigational treatments.
4. Concurrent systemic treatment with steroids or other immunosuppressant agents at a dose considered by the investigator to be higher than a standard physiological dose.
5. Evidence of severe or uncontrolled cardiac disease, including myocardial infarction or unstable angina within 6 months of screening, congestive heart failure, or ventricular arrhythmias requiring medication.
6. Diagnosed immunodeficiency or autoimmune disorder.
7. Infection with human immunodeficiency virus (HIV) or hepatitis C virus (HCV), or active and infectious hepatitis B virus (HBV) infection.
8. Pregnant or lactating.
9. Evidence or history of central nervous system metastasis.
10. Known hypersensitivity to any of the components of the study agent.
11. Any unresolved persistent toxicities from prior systemic therapy that are either Grade 3 or Grade 4 (except alopecia) per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
12. Intent to treat patient with both an anti-angiogenesis therapy (such as bevacizumab) and a poly (ADP-ribose) polymerase (PARP) inhibitor as part of maintenance therapy. Only one or the other are permitted while the patient is on study and must be started between the Baseline visit and Visit 1 (first treatment visit) if it will be used as part of the patient's maintenance therapy regimen.