Ovarian Cancer, Platinum Sensitive Ovarian Cancer
Conditions
Brief summary
This is a double-blind, randomized, parallel groups Phase II trial. Patients with platinum-sensitive advanced ovarian cancer, defined as a lack of progression by RECIST v1.1 criteria following completion of standard-of-care chemotherapy, including a minimum of 4 cycles of a platinum-containing regimen. Patients will be randomized to either the vaccine regimen with GM-CSF adjuvant or GM-CSF adjuvant alone as a control group. Treatment will be administered as a consolidation therapy within one year of the last administration of platinum, targeting the first remission.
Detailed description
This is a multicenter double-blind controlled randomized Phase II study to evaluate the activity of folate receptor alpha (FRα) peptide vaccine as a consolidation treatment following completion of no less than 4 cycles of a platinum containing regimen in patients with platinum-sensitive, non-mucinous ovarian, fallopian tube or primary peritoneal cancer. The patients will have demonstrated a tumor response or stable disease upon their last regimen (per RECIST v1.1 and/or CA125 GCIG criteria) prior to enrolment in this study. Following randomization, patients will be administered TPIV200 with GM-CSF adjuvant or GM-CSF control alone. Patients will have booster doses and tumor assessments done every 12 weeks ± 1 week for up to 1.5 years, until objective disease progression or the patient withdraws consent. Tumor responses will be assessed at the study sites by evaluating tumor images/scans according to RECIST v1.1.
Interventions
BIOLOGICALFRα peptide plus Adjuvant (GM-CSF)
Intradermal injection FRα peptides, 500μg each - plus GM-CSF 125 μg
DRUGAdjuvant (GM-CSF) Alone
Intradermal injection 125 μg GM-CSF
Sponsors
Marker Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Criteria for Inclusion: 1. Female patient ≥ 18 years 2. Willing and able to give informed consent 3. Stage III-IV platinum-sensitive (defined as a lack of progression by RECIST v1.1 criteria following completion of standard-of-care chemotherapy, including a minimum of 4 cycles of a platinum-containing regimen) epithelial ovarian, fallopian tube or primary peritoneal carcinoma in first remission. 4. Histologic documentation of diagnosis of carcinoma is required and the following histologic subtypes are eligible: high grade (grade ≥3+) serous or endometrioid carcinoma, carcinosarcoma, or poorly-differentiated adenocarcinoma, or mixed (including above subtypes only). Note that synchronous serous or endometrioid uterine or fallopian cancers are allowed. 5. The patient must have demonstrated an objective response (PR or CR) or stable disease (SD) with the last chemotherapy prior to enrollment and this response must be stable (without progressive disease) before randomization. 6. Patients must receive their first dose of vaccine within 1 year of completion of their final dose of a chemotherapeutic agent of the platinum-containing regimen 7. Adequate normal organ and marrow function within 14 days prior to first vaccine administration: * Absolute neutrophil count \> 1.5 x 109/L * Platelet \> 100 x 109/L * Hemoglobin \> 9.0 g/dL * Serum bilirubin \< 1.5 times ULN (unless Gilbert's syndrome without concurrent clinically significant liver disease * AST/ALT \< 2.5 ULN unless liver metastasis in which case it must be \< 5 x ULN * Serum creatinine CL \> 40 mL/min by Cockcroft-Gault formula. 8. Anti-nuclear antibody (ANA) negative or low-positive institutional range, as determined within 28 days from registration. Intermediate values (usually defined by a titer of ≤1:80, or as indicated by institutional range) are acceptable if there are, in the opinion of the Investigator, no early signs of an autoimmune disease. 9. Female subjects must either be of non-reproductive potential (i.e. post-menopause by history: \> 60 years old and no menses for \> 12 months naturally or secondary to radiation/chemotherapy; OR serum FSH, LH and estradiol levels in the post-menopausal range; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy), or must have a negative serum pregnancy test upon study entry 10. Life expectancy \> 24 weeks 11. ECOG performance status of 0 or 1 12. Formalin fixed, paraffin embedded tumor sample from the primary cancer must be sent for central testing. Criteria for Exclusion 1. Histology consistent with non-serous, non-endometrioid (i.e. mucinous or clear cell), or low-grade or borderline serous ovarian carcinoma 2. Patients with a history of other cancers (other than non-melanoma skin cancers \[i.e. basal or squamous cell\]) within the past 3 years. 3. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, targeted therapy, biological/cell therapy, tumor embolization, monoclonal antibodies, other investigational agent) \< 28 days prior to the first dose of study drug. 4. Current or prior use of immunosuppressive medication within 28 days prior to the fist dose of study drug with the exception of topical, intranasal or inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 5. Active autoimmune disease requiring therapy within the past 2 years. Note: patients with vitiligo, Grave's disease or psoriasis not requiring systemic treatment within the past 2 years are not excluded. 6. History of hypersensitivity to GM-CSF 7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent 8. Symptomatic thyroid disease, unless negative for thyroid antibodies (TSH receptor, TPO, thyroglobulin). 9. Subjects who are pregnant or are breast feeding. 10. Subjects who or of reproductive potential, and are either: * Not abstinent; * Not in an exclusive relationship with a partner who is surgically sterile; * Not employing an effective method of birth control. 11. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results 12. Symptomatic or uncontrolled brain metastasis requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids 13. Subject with uncontrolled seizures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 2 years | Time to disease progression or recurrence of ovarian cancer defined as disease progression by RECIST 1.1., disease recurrence, death without progression or CA125 progression |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 2 years | Death with or without ovarian cancer progression |
| Best Overall Response Rate | 2 years | Best overall response defined as sum of Complete Responses and Partial Responses in the subset of patients with measurable tumor lesions at baseline. Best overall response is a binary endpoint and defined as a best overall response of either CR or PR among subjects with measurable lesions at baseline, using RECIST v1.1. Disease control rate is the percentage of subjects with a response of CR, PR, or SD or non-CR/non-PR vs PD among subjects with measurable lesions at baseline. |
| Disease Control Rate | 2 years | Disease control rate defined as the sum of Complete Responses, Partial Responses and Stable Disease. Best overall response is a binary endpoint and defined as a best overall response of either CR or PR among subjects with measurable lesions at baseline, using RECIST v1.1. Disease control rate is the percentage of subjects with a response of CR, PR, or SD or non-CR/non-PR vs PD among subjects with measurable lesions at baseline. |
Countries
United States
Participant flow
Recruitment details
The first subject screened for trial 20 Jul 2017 and the last subject enrolled was screened 29Nov2018. Seventeen sites (academic and private clinics) in the United States enrolled and treated patients in the trial. The trial was terminated on 18 Oct 2019, after a blinded analysis by the DSMB determined that the futility requirements were not met. While the trial was terminated on 10/18/2019, the last patient could not return for a final visit/safety evaluation until January 15, 2020.
Pre-assignment details
Enrolled subjects were only excluded from the trial if it was found that inclusion/exclusion criteria were not met for continued participation.
Participants by arm
| Arm | Count |
|---|---|
| FRα Peptide Plus Adjuvant (GM-CSF) FRα peptide vaccine with GM-CSF adjuvant ID administration monthly for 6 months followed by booster administrations every 3 months for up to 1.5 years
FRα peptide plus Adjuvant (GM-CSF): Intradermal injection FRα peptides, 500μg each - plus GM-CSF 125 μg | 62 |
| Adjuvant (GM-CSF) Alone GM-CSF adjuvant alone ID administration monthly for 6 months followed by booster administrations every 3 months for up to 1.5 years
Adjuvant (GM-CSF) Alone: Intradermal injection 125 μg GM-CSF | 58 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Disease Progression | 32 | 32 |
| Overall Study | Early Study Termination | 24 | 21 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | FRα Peptide Plus Adjuvant (GM-CSF) | Total | Adjuvant (GM-CSF) Alone |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 46 Participants | 24 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants | 74 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 9 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 110 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| More than 6 months to last date of platinum therapy | 9 Participants | 12 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 55 Participants | 108 Participants | 53 Participants |
| Region of Enrollment United States | 62 participants | 120 participants | 58 participants |
| Sex: Female, Male Female | 62 Participants | 120 Participants | 58 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 62 | 1 / 58 |
| other Total, other adverse events | 61 / 62 | 56 / 58 |
| serious Total, serious adverse events | 8 / 62 | 8 / 58 |
Outcome results
Primary
Progression Free Survival
Time to disease progression or recurrence of ovarian cancer defined as disease progression by RECIST 1.1., disease recurrence, death without progression or CA125 progression
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FRα Peptide Plus Adjuvant (GM-CSF) | Progression Free Survival | 11.1 Months |
| Adjuvant (GM-CSF) Alone | Progression Free Survival | 10.9 Months |
Secondary
Best Overall Response Rate
Best overall response defined as sum of Complete Responses and Partial Responses in the subset of patients with measurable tumor lesions at baseline. Best overall response is a binary endpoint and defined as a best overall response of either CR or PR among subjects with measurable lesions at baseline, using RECIST v1.1. Disease control rate is the percentage of subjects with a response of CR, PR, or SD or non-CR/non-PR vs PD among subjects with measurable lesions at baseline.
Time frame: 2 years
Population: Subject in MITT with measurable disease at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FRα Peptide Plus Adjuvant (GM-CSF) | Best Overall Response Rate | 0 Participants |
| Adjuvant (GM-CSF) Alone | Best Overall Response Rate | 3 Participants |
Secondary
Disease Control Rate
Disease control rate defined as the sum of Complete Responses, Partial Responses and Stable Disease. Best overall response is a binary endpoint and defined as a best overall response of either CR or PR among subjects with measurable lesions at baseline, using RECIST v1.1. Disease control rate is the percentage of subjects with a response of CR, PR, or SD or non-CR/non-PR vs PD among subjects with measurable lesions at baseline.
Time frame: 2 years
Population: Subjects in MITT with measurable lesions at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FRα Peptide Plus Adjuvant (GM-CSF) | Disease Control Rate | 6 Participants |
| Adjuvant (GM-CSF) Alone | Disease Control Rate | 4 Participants |
Secondary
Overall Survival (OS)
Death with or without ovarian cancer progression
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FRα Peptide Plus Adjuvant (GM-CSF) | Overall Survival (OS) | NA Months |
| Adjuvant (GM-CSF) Alone | Overall Survival (OS) | NA Months |