Advanced Melanoma, Stage III Melanoma, Stage IV Melanoma
Conditions
Keywords
Pembrolizumab, All-Trans Retinoic Acid
Brief summary
This is a Phase I/Ib investigator-initiated open label of the combination of VESANOID and pembrolizumab treatment.
Detailed description
Primary Objective * To identify the MTD and RP2D of the combination of pembrolizumab and ATRA. Secondary Objective: * Describe the safety and toxicity of combined treatment with pembrolizumab and all-trans retinoic acid (ATRA) \[brand name VESANOID\] in melanoma patients. * To assess the anti-tumor activity in terms of a). The reduction in MDSC (immunosuppressive myeloid -derived suppressor cells) frequency and suppressive function (measured as a continuous variable)in peripheral blood of advanced melanoma patients undergoing pembrolizumab and VESANOID combination therapy. b). progression free survival. Exploratory Objective * To determine the clinical outcomes with tumor-specific T cell responses.
Interventions
DRUGPembrolizumab with All-Trans Retinoic Acid
All the patients will receive 200mg Q3W pembrolizumab treatment plus the supplemental treatment of 150 mg/m2 All-Trans Retinoic Acid orally for 3 days surrounding each of the first four infusions of pembrolizumab
Sponsors
Merck Sharp & Dohme LLC
University of Colorado, Denver
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of advanced melanoma (unresectable Stage III or Stage IV Melanoma). 2. Planned standard treatment with pembrolizumab. 3. Be willing and able to provide written informed consent for the trial. 4. State willingness to comply with all study procedures and be available for the duration of the trial. 5. Be ≥ 18 years of age on day of signing informed consent. 6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 7. Demonstrate adequate organ function as defined in Table 1 of the protocol. 8. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 9. Female subjects of childbearing potential (Section 6.5.2 - Contraception) must be willing to use an adequate method of contraception as outlined in Section 6.5.2 of the protocol - Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 10. Male subjects of childbearing potential (Section 6.5.2- Contraception) must agree to use an adequate method of contraception as outlined in Section 6.5.2 of the protocol - Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
Exclusion criteria
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 3. Has a known history of active TB (Bacillus Tuberculosis). 4. Hypersensitivity to pembrolizumab or any of its excipients. 5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Subjects with chronic conditions such as vision changes from plaque radiation therapy for ocular melanoma or prior hearing loss that is not reasonably expected to be exacerbated by the investigational product may be included. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 8. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 9. Has known history of, or any evidence of active, non-infectious pneumonitis. 10. Has an active infection requiring systemic therapy. 11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). 17. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. 18. Has known sensitivity to retinoic acid derivatives. 19. Has a medical history of allogenic stem cell transplant or received a solid organ transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximally Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of Pembrolizumab | 21 days from first dose of combined treatment | MTD is defined as the highest dose level with no more than 3 DLTs reported in 6 DLT-evaluable subjects. A target toxicity rate of approximately 33% of all 24 patients will be used to establish the RP2D. This is one part of the pembrolizumab-ATRA combination treatment. |
| Maximally Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of All-Trans Retinoic Acid | 21 days from first dose of combined treatment | MTD is defined as the highest dose level with no more than 3 DLT reported in 6 DLT-evaluable subjects. A target toxicity rate of approximately 33% of all 24 patients will be used to establish the RP2D. This dose is one part of the pembrolizumab-ATRA combination treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With a Dose-Limiting Toxicity (DLT) for the Combined Treatment of Pembrolizumab and All-Trans Retinoic Acid | 2 years | Toxicity is evaluated according to NCI CTCAE Version 4.0. A dose limiting toxicity (DLT) is defined as any grade 3 or higher adverse event related to VESNOID (the all-trans retinoic acid) and/or pembrolizumab. |
| Progression Free Survival | up to 36 months | Progression free survival was calculated from treatment start date to data cutoff date. |
| Percent Change in Anti-Tumor Activity | Pre-treatment (0-30 days before first ATRA administration) and post-treatment (84-130 days after first ATRA administration) | Anti-tumor activity will be determined by the percent change in MDSC (immunosuppressive myeloid-derived suppressor cells) frequency in peripheral blood of advanced melanoma patients undergoing the combined treatment of pembrolizumab and All-Trans Retinoic Acid (ATRA). Pre-treatment levels will be compared to post-treatment levels, where post-treatment means 4-6 weeks after stopping ATRA. MDSCs include CD45+, CD3-, CD19-, CD56-, CD11b+, CD33+, and HLA-DR-/low. In the original protocol, suppressive function was included as part of this outcome measure to assess anti-tumor activity. However, this analysis could not be performed because the decrease in concentration of MDSCs after treatment resulted in inadequate data for the planned assays. |
Countries
United States
Participant flow
Pre-assignment details
No de-escalation occurred. All subjects received 150 mg/m2 for 3 days before and after each of the first four infusions of pembrolizumab.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab With All-Trans Retinoic Acid Patients will receive pembrolizumab infusions every three weeks. Patients will also receive 3 days of all-trans retinoic acid treatment surrounding each of the first 4 infusions of pembrolizumab, beginning one day prior to the infusion (a total of 12 days of all-trans retinoic acid).
Pembrolizumab with All-Trans Retinoic Acid: All the patients will receive 200mg Q3W pembrolizumab treatment plus the supplemental treatment of 150 mg/m2 All-Trans Retinoic Acid orally for 3 days surrounding each of the first four infusions of pembrolizumab | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | Pembrolizumab With All-Trans Retinoic Acid |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 65.6 years STANDARD_DEVIATION 13.38843 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 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 | 1 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 25 |
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 12 / 25 |
Outcome results
Primary
Maximally Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of All-Trans Retinoic Acid
MTD is defined as the highest dose level with no more than 3 DLT reported in 6 DLT-evaluable subjects. A target toxicity rate of approximately 33% of all 24 patients will be used to establish the RP2D. This dose is one part of the pembrolizumab-ATRA combination treatment.
Time frame: 21 days from first dose of combined treatment
Population: The analysis population is 24 patients rather than 25 because one patient was not on treatment long enough to be evaluated for any outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab With All-Trans Retinoic Acid | Maximally Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of All-Trans Retinoic Acid | 150 mg/m2 |
Primary
Maximally Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of Pembrolizumab
MTD is defined as the highest dose level with no more than 3 DLTs reported in 6 DLT-evaluable subjects. A target toxicity rate of approximately 33% of all 24 patients will be used to establish the RP2D. This is one part of the pembrolizumab-ATRA combination treatment.
Time frame: 21 days from first dose of combined treatment
Population: The analysis population is 24 patients rather than 25 because one patient was not on treatment long enough to be evaluated for any outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab With All-Trans Retinoic Acid | Maximally Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of Pembrolizumab | 200 mg |
Secondary
Number of Patients With a Dose-Limiting Toxicity (DLT) for the Combined Treatment of Pembrolizumab and All-Trans Retinoic Acid
Toxicity is evaluated according to NCI CTCAE Version 4.0. A dose limiting toxicity (DLT) is defined as any grade 3 or higher adverse event related to VESNOID (the all-trans retinoic acid) and/or pembrolizumab.
Time frame: 2 years
Population: The analysis population is 24 patients rather than 25 because one patient was not on treatment long enough to be evaluated for any outcomes.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab With All-Trans Retinoic Acid | Number of Patients With a Dose-Limiting Toxicity (DLT) for the Combined Treatment of Pembrolizumab and All-Trans Retinoic Acid | 5 Participants |
Secondary
Percent Change in Anti-Tumor Activity
Anti-tumor activity will be determined by the percent change in MDSC (immunosuppressive myeloid-derived suppressor cells) frequency in peripheral blood of advanced melanoma patients undergoing the combined treatment of pembrolizumab and All-Trans Retinoic Acid (ATRA). Pre-treatment levels will be compared to post-treatment levels, where post-treatment means 4-6 weeks after stopping ATRA. MDSCs include CD45+, CD3-, CD19-, CD56-, CD11b+, CD33+, and HLA-DR-/low. In the original protocol, suppressive function was included as part of this outcome measure to assess anti-tumor activity. However, this analysis could not be performed because the decrease in concentration of MDSCs after treatment resulted in inadequate data for the planned assays.
Time frame: Pre-treatment (0-30 days before first ATRA administration) and post-treatment (84-130 days after first ATRA administration)
Population: Percent change in MDSC was computed both in total and separately for i) patients that responded to therapy, and ii) patients that did not respond to therapy. Response was evaluated using RECIST v1.1 criteria. The analysis population for this outcome measure is 23 patients because one patient did not complete a post-treatment blood draw.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pembrolizumab With All-Trans Retinoic Acid | Percent Change in Anti-Tumor Activity | Responding patients | -48.6 percent change from pre-treatment value | Standard Deviation 54.4 |
| Pembrolizumab With All-Trans Retinoic Acid | Percent Change in Anti-Tumor Activity | Non-responding patients | 109.7 percent change from pre-treatment value | Standard Deviation 224.6 |
| Pembrolizumab With All-Trans Retinoic Acid | Percent Change in Anti-Tumor Activity | Overall | -7.3 percent change from pre-treatment value | Standard Deviation 136.6 |
Secondary
Progression Free Survival
Progression free survival was calculated from treatment start date to data cutoff date.
Time frame: up to 36 months
Population: The analysis population is 24 patients rather than 25 because one patient was not on treatment long enough to be evaluated for any outcomes.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab With All-Trans Retinoic Acid | Progression Free Survival | 20.3 months |