Colorectal Cancer
Conditions
Brief summary
Phase I/II clinical trial investigates the safety, tolerability, immunogenicity and preliminary efficacy of multiple doses of PolyPEPI1018 CRC vaccine as an add-on treatment to the standard-of-care maintenance therapy in patients with metastatic colorectal cancer. Clinical responses will be evaluated by indiction of T cell responses, T lymphocyte infiltration in accessible biopsy sites, and by objective tumor responses. This study will also explore the accuracy of the predicted T cell responses in each patient using the candidate companion diagnostic test and the correlations between clinical responses and predicted T cell responses.
Detailed description
This is a Phase I/II, open-label, single-arm, multicenter study to evaluate the safety, tolerability, immunogenicity and efficacy of a multiple subcutaneous injection of PolyPEPI1018 as an add-on immunotherapy to the standard-of-care maintenance therapy in approximately 15 subjects with metastatic colorectal cancer. The first part of the study investigates the administration of a single vaccine dose during 12-week follow-up period on an outpatient basis. Screening is performed in parallel with the subject's completion of the standard-of-care first-line treatment and initiation of the standard-of-care maintenance treatment. A single dose of PolyPEPI1018 is administered after the subject initiates the maintenance regimen, and within 3 weeks after the eligibility CT scan was performed. Subjects are monitored every 3 weeks for 12 weeks. The second part of the study investigates the administration of 3 vaccine doses (Weeks 0, 13, 26) then 12 weeks follow-up on an outpatient basis.
Interventions
BIOLOGICALPolyPEPI1018 CRC Vaccine
Colorectal Cancer Vaccine
Sponsors
Mayo Clinic
University of Pisa
Laboratory Corporation of America
PPD Development, LP
ImmunXperts SA
Treos Bio Zrt
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female subjects, 18-75 years of age at time of Screening who provide written informed consent prior to initiation of any study procedure 2. Histologically confirmed metastatic adenocarcinoma originating from the colon or the rectum 3. Presence of at least 1 measurable reference lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria 4. Experienced PR or stable disease during first-line treatment with a systemic chemotherapy regimen and 1 biological therapy regimen 5. Maintenance therapy with a fluoropyrimidine (5-fluorouracil or capecitabine) plus the same biologic agent (bevacizumab, cetuximab or panitumumab) used during induction, scheduled to initiate prior to the first day of treatment with the study drug 6. No more than 1 line of chemotherapy regimen for mCRC (adjuvant therapy for non-metastasized disease is allowed if terminated more than 6 months before Screening and without recurrence within 6 months after the end of adjuvant treatment) 7. Last CT scan at 3 weeks or less before the first day of treatment 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 9. Women of childbearing potential must agree to appropriately use an effective form of contraception (failure rate of \<1% per year) for 3 months from the day of the treatment. An effective form of contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, cervical cap or condom 10. Men must agree to use an effective form of contraception (as defined above), and not donate sperm for 3 months from the day of the treatment 11. White blood cell count ≥3.0 × 109/L with neutrophils ≥1.5 × 109/L 12. Platelets ≥100 × 109/L, hemoglobin ≥5.6 mmol/L (corresponding to 9 g/dL) 13. Serum bilirubin ≤1.5 × upper limit of normal (ULN) set by the site 14. Alanine amino transferase (ALAT) and aspartate amino transferase (ASAT) ≤2.5 × ULN in the absence of liver metastases. ALAT and ASAT ≤5 × ULN set by the site in the presence of liver metastases 15. Serum creatinine ≤1.5 × ULN set by the site and creatinine clearance \>30 mL/min using Cockroft formula 16. Relevant toxicities of prior therapies must have resolved, except for oxaliplatin-related neuropathy or alopecia 17. Anticipated life expectancy ≥6 months Subject is willing and able to comply with the requirements of the protocol
Exclusion criteria
1. Received chronic systemic immune therapy or immunosuppressant medication other than steroids within the last 6 weeks prior to start of study treatment 2. Received continuous systemic steroid treatment within the last 2 weeks prior to start of study treatment 3. Colorectal cancer with documented high microsatellite instability (MSI-H) 4. Colorectal cancer with documented BRAF mutations 5. Pre-existing systemic autoimmune or antibody-mediated diseases or immune deficiency diseases 6. Central nervous system (CNS) metastases 7. Active or uncontrolled severe infections or undiagnosed febrile condition \>38ºC 8. Acute or subacute intestinal obstruction or history of chronic intestinal inflammatory diseases 9. Symptomatic peritoneal carcinomatosis 10. Peritonitis 11. Serious, non-healing wounds, ulcers or bone fractures 12. Nephrotic syndrome 13. Arterial thromboembolisms or severe hemorrhages within 6 months before study enrolment (except bleeding tumor before tumor resection surgery) 14. Hemorrhagic diathesis or thrombotic tendency 15. Major surgery or radiotherapy within 12 weeks prior to the study treatment or anticipation of needing such procedure during the study period 16. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage more than once every 28 days 17. Participants with active malignancy (other than colorectal cancer) or a prior malignancy within the past 12 months 18. Participant with myocardial infarction within 6 months prior to enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to the first dose of study treatment, any electrocardiogram (ECG) abnormality at Screening must be documented by the investigator as not medically relevant 19. Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation of a live attenuated vaccine will be required during the study 20. Participant has participated in another clinical study involving an investigational product (IP) or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study 21. Known hypersensitivity to any component of the investigational drug 22. If female, participant is pregnant (exclusion confirmed with beta-human chorionic gonadotropin \[hCG\] test) or lactating at the time of enrollment, or has plans to become pregnant or start breastfeeding during the study 23. Pre-existing alcohol or drug abuse 24. Medical or mental impairments which make it impossible to obtain the patient's consent or to conduct the study 25. A significant concomitant medical condition which the clinical investigator believes precludes the patient from enrolling in the study Absent or limited legal competence
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Related Adverse Events | from 1st vaccination to 21 days after last vaccinations, up to 41 weeks | Occurrence of at least 1 ≥Grade 4 local adverse event (AE) or 1 ≥Grade 3 systemic AE and/or signs/symptoms, lab toxicities, and/or clinical events that is probably or definitely related to study treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Having T Cell Immune Response | 12 weeks | Measured CD4+ and CD8+ T cell responses from each subject for each antigen of the vaccine |
| Number of Predicted Antigen Specific T Cell Responses Per Patient | 21 days | Epitopes restricted to multiple HLA class I alleles (Personal Epitope, PEPI) of a subject were predicted. PEPIs determined for each vaccine antigen can predict the antigen-specific T cell responses for each patient. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Objective Tumor Responses - Objective Response Rate (RECIST v1.1) | 12 weeks | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. CT scans were performed at screening and weeks 6,12 after each vaccination. The objective response were based on for each subject's last CT scan evaluation. |
| Number of Participants With Objective Tumor Responses - Disease Control Rate (Best Overall Response is Partial Response or Stable Disease) | 12 weeks | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) \<30% increase compare to smallest sum of the longest diameter of target lesions. CT scans were performed at screening and weeks 6,12 after each vaccination. The DCR were counted as the best response (PR or SD) for each subject's during the trial. |
| Number of Participants Having Induced Recruitment of TILs | Last visit, up to 38 weeks | Assessments of TILs was performed using IHC (Immunoscore CR) CD3/CD8 testing on liver biopsy tissue samples obtained from subjects during a time course from baseline until the Last Visit. The CD3+ and CD8+ cell densities were determined in the core tumor and invasive margin using Immunohistochemistry (IHC) staining followed by digital pathology. |
Countries
Italy, United States
Participant flow
Recruitment details
The participants were recruited based on physicians referral at two medical centers between May and Dec 2018. The first subject was enrolled on 3 May 2018 and the last subject was enrolled on 13 Dec 2018.
Pre-assignment details
Of 13 screened participants 11 met the inclusion criteria and were enrolled and treated. One of the two not enrolled subjects were over 75 years (IN01), and the other had the last CT scan over 3 weeks (IN07). All 11 subjects started and completed Part A to get the first dose and 6 of them continued treatment in Part B for additional doses (Amended protocol).
Participants by arm
| Arm | Count |
|---|---|
| Single Dose of PolyPEPI1018 CRC Vaccine The subjects were treated with only one dose PolyPEPI1018 CRC vaccine. | 5 |
| Multiple Dose of PolyPEPI1018 CRC Vaccine The subjects received 2 or 3 doses PolyPEPI1018 CRC vaccine. | 6 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part B - Additional 2 Doses (13-38weeks) | Physician Decision | 0 | 1 |
| Part B - Additional 2 Doses (13-38weeks) | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Multiple Dose of PolyPEPI1018 CRC Vaccine | Single Dose of PolyPEPI1018 CRC Vaccine | Total |
|---|---|---|---|
| Age, Continuous | 47.5 years STANDARD_DEVIATION 6 | 64.8 years STANDARD_DEVIATION 5.3 | 55.4 years STANDARD_DEVIATION 10.5 |
| Height | 185.9 cm STANDARD_DEVIATION 9.6 | 160.0 cm STANDARD_DEVIATION 33.7 | 174.1 cm STANDARD_DEVIATION 26.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 5 Participants | 11 Participants |
| Region of Enrollment Italy | 0 participants | 4 participants | 4 participants |
| Region of Enrollment United States | 6 participants | 1 participants | 7 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
| Weight | 95.7 Kg STANDARD_DEVIATION 24.9 | 82.6 Kg STANDARD_DEVIATION 13.2 | 89.7 Kg STANDARD_DEVIATION 20.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 6 |
| other Total, other adverse events | 2 / 5 | 6 / 6 |
| serious Total, serious adverse events | 1 / 5 | 2 / 6 |
Outcome results
Primary
Number of Participants With Treatment Related Adverse Events
Occurrence of at least 1 ≥Grade 4 local adverse event (AE) or 1 ≥Grade 3 systemic AE and/or signs/symptoms, lab toxicities, and/or clinical events that is probably or definitely related to study treatment
Time frame: from 1st vaccination to 21 days after last vaccinations, up to 41 weeks
Population: All subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Dose of PolyPEPI1018 CRC Vaccine | Number of Participants With Treatment Related Adverse Events | 0 Participants |
| Multiple Dose of PolyPEPI1018 CRC Vaccine | Number of Participants With Treatment Related Adverse Events | 0 Participants |
Secondary
Number of Participants Having T Cell Immune Response
Measured CD4+ and CD8+ T cell responses from each subject for each antigen of the vaccine
Time frame: 12 weeks
Population: Ten of 11 subject had sufficient PBMC samples to evaluate T cell responses
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Dose of PolyPEPI1018 CRC Vaccine | Number of Participants Having T Cell Immune Response | CD4+ T cell responses | 4 Participants |
| Single Dose of PolyPEPI1018 CRC Vaccine | Number of Participants Having T Cell Immune Response | CD8+ T cell responses against 3 or more AG | 4 Participants |
| Single Dose of PolyPEPI1018 CRC Vaccine | Number of Participants Having T Cell Immune Response | CD8+ T cell responses | 4 Participants |
| Single Dose of PolyPEPI1018 CRC Vaccine | Number of Participants Having T Cell Immune Response | Booth CD4+ and CD8+ T cell responses | 4 Participants |
| Multiple Dose of PolyPEPI1018 CRC Vaccine | Number of Participants Having T Cell Immune Response | CD8+ T cell responses | 5 Participants |
| Multiple Dose of PolyPEPI1018 CRC Vaccine | Number of Participants Having T Cell Immune Response | CD4+ T cell responses | 6 Participants |
| Multiple Dose of PolyPEPI1018 CRC Vaccine | Number of Participants Having T Cell Immune Response | Booth CD4+ and CD8+ T cell responses | 5 Participants |
| Multiple Dose of PolyPEPI1018 CRC Vaccine | Number of Participants Having T Cell Immune Response | CD8+ T cell responses against 3 or more AG | 4 Participants |
Secondary
Number of Predicted Antigen Specific T Cell Responses Per Patient
Epitopes restricted to multiple HLA class I alleles (Personal Epitope, PEPI) of a subject were predicted. PEPIs determined for each vaccine antigen can predict the antigen-specific T cell responses for each patient.
Time frame: 21 days
Population: All subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Dose of PolyPEPI1018 CRC Vaccine | Number of Predicted Antigen Specific T Cell Responses Per Patient | 4.80 predicted PEPIs | Standard Deviation 1.64 |
| Multiple Dose of PolyPEPI1018 CRC Vaccine | Number of Predicted Antigen Specific T Cell Responses Per Patient | 4.17 predicted PEPIs | Standard Deviation 1.33 |
Other Pre-specified
Number of Participants Having Induced Recruitment of TILs
Assessments of TILs was performed using IHC (Immunoscore CR) CD3/CD8 testing on liver biopsy tissue samples obtained from subjects during a time course from baseline until the Last Visit. The CD3+ and CD8+ cell densities were determined in the core tumor and invasive margin using Immunohistochemistry (IHC) staining followed by digital pathology.
Time frame: Last visit, up to 38 weeks
Population: Only subjects who had tissue-pairs for TIL measurements (4 of 11).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Dose of PolyPEPI1018 CRC Vaccine | Number of Participants Having Induced Recruitment of TILs | 1 Participants |
| Multiple Dose of PolyPEPI1018 CRC Vaccine | Number of Participants Having Induced Recruitment of TILs | 2 Participants |
Other Pre-specified
Number of Participants With Objective Tumor Responses - Disease Control Rate (Best Overall Response is Partial Response or Stable Disease)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) \<30% increase compare to smallest sum of the longest diameter of target lesions. CT scans were performed at screening and weeks 6,12 after each vaccination. The DCR were counted as the best response (PR or SD) for each subject's during the trial.
Time frame: 12 weeks
Population: Full set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Dose of PolyPEPI1018 CRC Vaccine | Number of Participants With Objective Tumor Responses - Disease Control Rate (Best Overall Response is Partial Response or Stable Disease) | 4 Participants |
| Multiple Dose of PolyPEPI1018 CRC Vaccine | Number of Participants With Objective Tumor Responses - Disease Control Rate (Best Overall Response is Partial Response or Stable Disease) | 5 Participants |
Other Pre-specified
Number of Participants With Objective Tumor Responses - Objective Response Rate (RECIST v1.1)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. CT scans were performed at screening and weeks 6,12 after each vaccination. The objective response were based on for each subject's last CT scan evaluation.
Time frame: 12 weeks
Population: Full set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Dose of PolyPEPI1018 CRC Vaccine | Number of Participants With Objective Tumor Responses - Objective Response Rate (RECIST v1.1) | 1 Participants |
| Multiple Dose of PolyPEPI1018 CRC Vaccine | Number of Participants With Objective Tumor Responses - Objective Response Rate (RECIST v1.1) | 2 Participants |