Cervical Cancer
Conditions
Keywords
KEYTRUDA®, pembrolizumab, GX-188E, TDS-IM device, KEYNOTE-567
Brief summary
A Multi-Center, Open-label Phase Ib-II Trial of the Combination of GX-188E Vaccination and Pembrolizumab in Patients with Advanced, Non-Resectable HPV-Positive Cervical Cancer
Detailed description
This is an open-label Phase Ib-II trial to evaluate the safety and efficacy of GX-188E (IM administration using Ichor TDS-IM device) + pembrolizumab (P) in patients with advanced HPV-16+ or HPV-18+ cervical cancer.
Interventions
Sponsors
Merck Sharp & Dohme LLC
Genexine, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must be female and age ≥ 18 years (19 years for Korean sites) 2. Patients with histologically confirmed advanced or metastatic HPV-positive (HPV-16 or HPV-18) cervical cancer, who have disease progression after treatment with all available therapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 4. Life Expectancy of at least 6 months 5. Patients must agree to provide either an archival tumor tissue sample or fresh biopsy sample for baseline biomarker tissue analyses, including staining for PD-L1. If archival tissue is not available and the patient does not have biopsy-accessible tumor lesions, the patient will be excluded.
Exclusion criteria
1. Patient has disease that is suitable for local therapy administered with curative intent. 2. Patient has a known additional malignancy that is progressing or has required active treatment within the past 3 years. 3. Patient is expected to require any other form of antineoplastic therapy while on study; including systemic chemotherapy, radiation therapy (except for palliative purposes) biological therapy, or immunotherapy not specified in this protocol. 4. Patient has a history of active central nervous system (CNS) metastases and/or carcinomatous meningitis. 5. Patients have received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related Adverse Event (irAE) 6. Patients with active autoimmune disease requiring systemic immunosuppressive treatment within the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. 7. Patients has had an allogeneic solid organ or allogeneic bone marrow transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DLT Evaluation for Safety and Tolerability(Part A) | within 21days | Patient will be evaluated for the first 21 days for dose-limiting toxicities. |
| ORR for Efficacy (Part B&C) | within 24 weeks | ORR within 24 weeks (ORR24) evaluated by RECIST v1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-Best Response | up to 1 year | Time-to-Best Response by RECIST v1.1 and iRECIST |
| Duration of Response (DOR) | up to 1 year | Duration of Response (DOR) by RECIST v1.1 and iRECIST |
| ORR for Efficacy (Part A) | within 24 weeks | Overall Response Rate within 24 weeks (ORR24) by RECIST v1.1 and immune-related Response Criteria (irRC) |
| Overall Survival (OS) | up to 1 year | Overall Survival (OS) by RECIST v1.1 and iRECIST |
| Progression-Free Survival (PFS) | up to 6 months | 6month- PFS by RECIST v1.1 and iRECIST |
| BORR (Part B&C) | up to 1 year | Best Overall Response Rate(BORR) by RECIST v1.1 |
Countries
South Korea
Participant flow
Recruitment details
A total of 90 subjects were enrolled, of which 25 subjects were considered as screen failures. Of 90 Screened, 65 met Inclusion/Exclusion Criteria and were Randomized to treatment.
Pre-assignment details
Subjects were enrolled in three Parts; 6 subjects in Part A, 31 subjects in Part B (6 rolled over from Part A to Part B) and 65 subjects in Part C (6 rolled over from Part A and 25 from Part B) were enrolled. Of the 25 subjects enrolled during Part B period, 1 subject completed Part B and rolled over to Part C to continue the study, but died during Part C period. Therefore, this subject was counted as 'Completed' for Part B period, but 'Not Completed due to Death' for Part C period.
Participants by arm
| Arm | Count |
|---|---|
| GX-188E, KEYTRUDA® GX-188E: 1st day of week 1,2,4,7,13,19, 46/ 2mg KEYTRUDA® : Day 1 q3 weeks/ 200mg
GX-188E: GX-188E (1.0mg/0.5ml/vial), Intramuscular administration using electroporator, Ichor TDS-IM device
KEYTRUDA®: pembrolizumab(100mg/4mL/vial), Intravenous administration | 65 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part A | Adverse Event | 1 |
| Part A | Disease relapse or Progression | 1 |
| Part A | Withdrawal by Subject | 2 |
| Part B | Adverse Event | 2 |
| Part B | Disease relapse or Progression | 18 |
| Part B | Physician Decision | 1 |
| Part B | Withdrawal by Subject | 2 |
| Part C | Adverse Event | 2 |
| Part C | Death | 1 |
| Part C | Disease relapse or Progression | 43 |
| Part C | Physician Decision | 2 |
| Part C | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | GX-188E, KEYTRUDA® |
|---|---|
| Age, Categorical Part A <=18 years | 0 Participants |
| Age, Categorical Part A >=65 years | 1 Participants |
| Age, Categorical Part A Between 18 and 65 years | 5 Participants |
| Age, Categorical Part B <=18 years | 0 Participants |
| Age, Categorical Part B >=65 years | 2 Participants |
| Age, Categorical Part B Between 18 and 65 years | 29 Participants |
| Age, Categorical Part C <=18 years | 0 Participants |
| Age, Categorical Part C >=65 years | 6 Participants |
| Age, Categorical Part C Between 18 and 65 years | 59 Participants |
| Histologic Type Part A Adenocarcinoma | 3 Participants |
| Histologic Type Part A Squamous Cell Carcinoma | 3 Participants |
| Histologic Type Part B Adenocarcinoma | 8 Participants |
| Histologic Type Part B Squamous Cell Carcinoma | 23 Participants |
| Histologic Type Part C Adenocarcinoma | 15 Participants |
| Histologic Type Part C Squamous Cell Carcinoma | 50 Participants |
| HPV type Part A HPV-16 | 3 Participants |
| HPV type Part A HPV-18 or both | 3 Participants |
| HPV type Part B HPV-16 | 24 Participants |
| HPV type Part B HPV-18 or both | 7 Participants |
| HPV type Part C HPV-16 | 49 Participants |
| HPV type Part C HPV-18 or both | 16 Participants |
| PD-L1 expression status Part A Negative (<1 CPS) | 6 Participants |
| PD-L1 expression status Part A Positive (≥1 CPS) | 0 Participants |
| PD-L1 expression status Part B Negative (<1 CPS) | 16 Participants |
| PD-L1 expression status Part B Positive (≥1 CPS) | 15 Participants |
| PD-L1 expression status Part C Negative (<1 CPS) | 26 Participants |
| PD-L1 expression status Part C Positive (≥1 CPS) | 39 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 65 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 65 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 31 / 65 |
| other Total, other adverse events | 54 / 65 |
| serious Total, serious adverse events | 25 / 65 |
Outcome results
Primary
DLT Evaluation for Safety and Tolerability(Part A)
Patient will be evaluated for the first 21 days for dose-limiting toxicities.
Time frame: within 21days
Population: The first 6 subjects (Part A) were enrolled and evaluated for the first 3 weeks (prior to Week 4 Day 1 visit) for DLTs. No additional subjects were enrolled until all subjects in Part A completed the DLT window and the investigational treatment regimen was deemed safe.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GX-188E, KEYTRUDA® | DLT Evaluation for Safety and Tolerability(Part A) | 0 participants |
Primary
ORR for Efficacy (Part B&C)
ORR within 24 weeks (ORR24) evaluated by RECIST v1.1
Time frame: within 24 weeks
Population: All efficacy analyses included 60 subjects from the Efficacy Evaluable Population. Safety analyses included 65 subjects. Five subjects were excluded from efficacy analysis for receiving less than 45 days of treatment without experiencing any DLT. The efficacy population comprised 6 subjects in Part A, 29 in Part B (including 6 from Part A), and 60 in Part C (including 6 from Part A and 23 from Part B).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GX-188E, KEYTRUDA® | ORR for Efficacy (Part B&C) | Part B | 41.4 percentage of responders |
| GX-188E, KEYTRUDA® | ORR for Efficacy (Part B&C) | Part C | 35.0 percentage of responders |
Secondary
BORR (Part B&C)
Best Overall Response Rate(BORR) by RECIST v1.1
Time frame: up to 1 year
Population: All efficacy analyses included 60 subjects from the Efficacy Evaluable Population. Safety analyses included 65 subjects. Five subjects were excluded from efficacy analysis for receiving less than 45 days of treatment without experiencing any DLT. The efficacy population comprised 6 subjects in Part A, 29 in Part B (including 6 from Part A), and 60 in Part C (including 6 from Part A and 23 from Part B).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GX-188E, KEYTRUDA® | BORR (Part B&C) | Part A | 50.0 percentage of responders |
| GX-188E, KEYTRUDA® | BORR (Part B&C) | Part B | 41.4 percentage of responders |
| GX-188E, KEYTRUDA® | BORR (Part B&C) | Part C | 35.0 percentage of responders |
Secondary
Duration of Response (DOR)
Duration of Response (DOR) by RECIST v1.1 and iRECIST
Time frame: up to 1 year
Population: All efficacy analyses included 60 subjects from the Efficacy Evaluable Population. Safety analyses included 65 subjects. Five subjects were excluded from efficacy analysis for receiving less than 45 days of treatment without experiencing any DLT. The efficacy population comprised 6 subjects in Part A, 29 in Part B (including 6 from Part A), and 60 in Part C (including 6 from Part A and 23 from Part B).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GX-188E, KEYTRUDA® | Duration of Response (DOR) | Part A | NA Months |
| GX-188E, KEYTRUDA® | Duration of Response (DOR) | Part B | 5.78 Months |
| GX-188E, KEYTRUDA® | Duration of Response (DOR) | Part C | NA Months |
Secondary
ORR for Efficacy (Part A)
Overall Response Rate within 24 weeks (ORR24) by RECIST v1.1 and immune-related Response Criteria (irRC)
Time frame: within 24 weeks
Population: All efficacy analyses were carried out using the 60 in the Efficacy Evaluable Population, respectively, and ORR24 analysis was performed for 6 subjects in the Part A group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GX-188E, KEYTRUDA® | ORR for Efficacy (Part A) | 50.0 percentage of responders |
Secondary
Overall Survival (OS)
Overall Survival (OS) by RECIST v1.1 and iRECIST
Time frame: up to 1 year
Population: All efficacy analyses included 60 subjects from the Efficacy Evaluable Population. Safety analyses included 65 subjects. Five subjects were excluded from efficacy analysis for receiving less than 45 days of treatment without experiencing any DLT. The efficacy population comprised 6 subjects in Part A, 29 in Part B (including 6 from Part A), and 60 in Part C (including 6 from Part A and 23 from Part B).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GX-188E, KEYTRUDA® | Overall Survival (OS) | Part A | 15.54 Months |
| GX-188E, KEYTRUDA® | Overall Survival (OS) | Part B | 14.42 Months |
| GX-188E, KEYTRUDA® | Overall Survival (OS) | Part C | 23.79 Months |
Secondary
Progression-Free Survival (PFS)
6month- PFS by RECIST v1.1 and iRECIST
Time frame: up to 6 months
Population: All efficacy analyses included 60 subjects from the Efficacy Evaluable Population. Safety analyses included 65 subjects. Five subjects were excluded from efficacy analysis for receiving less than 45 days of treatment without experiencing any DLT. The efficacy population comprised 6 subjects in Part A, 29 in Part B (including 6 from Part A), and 60 in Part C (including 6 from Part A and 23 from Part B).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GX-188E, KEYTRUDA® | Progression-Free Survival (PFS) | Part A | 4.25 Months |
| GX-188E, KEYTRUDA® | Progression-Free Survival (PFS) | Part B | 4.14 Months |
| GX-188E, KEYTRUDA® | Progression-Free Survival (PFS) | Part C | 4.40 Months |
Secondary
Time-to-Best Response
Time-to-Best Response by RECIST v1.1 and iRECIST
Time frame: up to 1 year
Population: All efficacy analyses included 60 subjects from the Efficacy Evaluable Population. Safety analyses included 65 subjects. Five subjects were excluded from efficacy analysis for receiving less than 45 days of treatment without experiencing any DLT. The efficacy population comprised 6 subjects in Part A, 29 in Part B (including 6 from Part A), and 60 in Part C (including 6 from Part A and 23 from Part B).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GX-188E, KEYTRUDA® | Time-to-Best Response | Part A | 2.07 Months |
| GX-188E, KEYTRUDA® | Time-to-Best Response | Part B | 2.10 Months |
| GX-188E, KEYTRUDA® | Time-to-Best Response | Part C | 2.10 Months |