Stage IV MelanomaPhase 1/2NCT03200847
Pembrolizumab and All-Trans Retinoic Acid Combination Treatment of Advanced Melanoma
A Phase 1/2 study testing Pembrolizumab with All-Trans Retinoic Acid in people with Stage IV Melanoma and Stage III Melanoma, run by University of Colorado, Denver at 2 sites in United States.
Trial summary
This is a Phase I/Ib investigator-initiated open label of the combination of VESANOID and pembrolizumab treatment. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Stage IV Melanoma, Stage III Melanoma, Advanced Melanoma
- What is being tested?
- Pembrolizumab with All-Trans Retinoic Acid
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 26 participants
- Where
- 2 sitesUnited States
- Study dates
- 31 Oct 2017to 19 Oct 2022
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of advanced melanoma (unresectable Stage III or Stage IV Melanoma).
- Planned standard treatment with pembrolizumab.
- Be willing and able to provide written informed consent for the trial.
- State willingness to comply with all study procedures and be available for the duration of the trial.
- Be ≥ 18 years of age on day of signing informed consent.
- Have a performance status of 0 or 1 on the ECOG Performance Scale.
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- Demonstrate adequate organ function as defined in Table 1 of the protocol.
- 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.
- 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.
- 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.
Who cannot join
- 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.
- 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.
- Has a known history of active TB (Bacillus Tuberculosis).
- Hypersensitivity to pembrolizumab or any of its excipients.
- 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.
- 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.
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- 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.
- 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.
- 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.
- Has known history of, or any evidence of active, non-infectious pneumonitis.
- Has an active infection requiring systemic therapy.
- 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.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- 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.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- 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.
- Has known sensitivity to retinoic acid derivatives.
- Has a medical history of allogenic stem cell transplant or received a solid organ transplant.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of Colorado Denver
Aurora, Colorado, 80045
Poudre Valley Hospital
Fort Collins, Colorado, 80528
About this study
Official title: Pembrolizumab and All-Trans Retinoic Acid in Combination Treatment of Advanced Melanoma
This is a Phase I/Ib investigator-initiated open label of the combination of VESANOID and pembrolizumab treatment.
Read the 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.
- Conditions
- Stage IV Melanoma, Stage III Melanoma, Advanced Melanoma
- Being tested
- Pembrolizumab with All-Trans Retinoic Acid
- Keywords
- Pembrolizumab, All-Trans Retinoic Acid
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Pembrolizumab with All-Trans Retinoic AcidDrug
Also called VESANOID, Keytruda
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
| Study group | Role | What they receive |
|---|---|---|
| Pembrolizumab with All-Trans Retinoic Acid | Experimental | 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). Receives: Drug: Pembrolizumab with All-Trans Retinoic Acid |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 21 days from first dose of combined treatment
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.
Measured: 21 days from first dose of combined treatment
Secondary outcomes (3)
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.
Measured: 2 years
Progression Free Survival
Progression free survival was calculated from treatment start date to data cutoff date.
Measured: up to 36 months
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.
Measured: Pre-treatment (0-30 days before first ATRA administration) and post-treatment (84-130 days after first ATRA administration)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jun 2017
- Study start31 Oct 2017
- Primary completion20 Jul 2022
- Study completion19 Oct 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Stage IV MelanomaStudies of the same condition, open and under way.
- More trials run by University of Colorado, DenverThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Colorado, Denver
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
- Investigators
- Martin McCarter, MD, Principal investigator, University of Colorado, Denver
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03200847
- Sponsor's protocol ID
- 16-1080.cc
- Other IDs
- PMID 36378549
- Status last verified
- Sep 2024
- First submitted
- 23 Jun 2017
- Last updated
- 1 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Tobin RP, Cogswell DT, Cates VM, Davis DM, Borgers JSW, Van Gulick RJ, Katsnelson E, Couts KL, Jordan KR, Gao D, Davila E, Medina TM, Lewis KD, Gonzalez R, McFarland RW, Robinson WA, McCarter MD. Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma. Clin Cancer Res. 2023 Apr 3;29(7):1209-1219. doi: 10.1158/1078-0432.CCR-22-2495.
PubMed 36378549
Study at a glance
From the registry record, last updated by the sponsor on 1 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pembrolizumab and All-Trans Retinoic Acid in Combination Treatment of Advanced Melanoma
- ClinicalTrials.gov ID
- NCT03200847
- Acronym / sponsor ID
- 16-1080.cc
- Conditions
- Stage IV Melanoma, Stage III Melanoma, Advanced Melanoma
- Keywords
- Pembrolizumab, All-Trans Retinoic Acid
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 26 participants (actual)
- Lead sponsor
- University of Colorado, DenverUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 31 Oct 2017 (actual)
- Primary completion
- 20 Jul 2022 (actual)
- Study completion
- 19 Oct 2022 (actual)
- First posted
- 27 Jun 2017 (actual)
- Results
- Posted 2 Mar 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pembrolizumab with All-Trans Retinoic Acid | Experimental | Drug: Pembrolizumab with All-Trans Retinoic AcidPatients 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). |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Diagnosis of advanced melanoma (unresectable Stage III or Stage IV Melanoma).
- Planned standard treatment with pembrolizumab.
- Be willing and able to provide written informed consent for the trial.
- State willingness to comply with all study procedures and be available for the duration of the trial.
- Be ≥ 18 years of age on day of signing informed consent.
Key exclusion criteria (21 listed)
- 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.
- 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.
- Has a known history of active TB (Bacillus Tuberculosis).
- Hypersensitivity to pembrolizumab or any of its excipients.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pembrolizumab with All-Trans Retinoic AcidAlso: VESANOID, KeytrudaAll 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 | Drug | Pembrolizumab with All-Trans Retinoic Acid |
Primary outcome
Maximally Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of Pembrolizumab
Time frame: 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
Time frame: 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.
3 secondary outcomes
Number of Patients With a Dose-Limiting Toxicity (DLT) for the Combined Treatment of Pembrolizumab and All-Trans Retinoic Acid
Time frame: 2 years
Progression Free Survival
Time frame: up to 36 months
Percent Change in Anti-Tumor Activity
Time frame: Pre-treatment (0-30 days before first ATRA administration) and post-treatment (84-130 days after first ATRA administration)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 36378549Tobin RP, Cogswell DT, Cates VM, Davis DM, Borgers JSW, Van Gulick RJ, Katsnelson E, Couts KL, Jordan KR, Gao D, Davila E, Medina TM, Lewis KD, Gonzalez R, McFarland RW, Robinson WA, McCarter MD. Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma. Clin Cancer Res. 2023 Apr 3;29(7):1209-1219. doi: 10.1158/1078-0432.CCR-22-2495.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Martin McCarter, MD principal investigator
University of Colorado, Denver
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Pembrolizumab with All-Trans Retinoic Acid in people with Stage IV Melanoma and Stage III Melanoma, run by University of Colorado, Denver at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Mar 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximally Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of Pembrolizumab (time frame: 21 days from first dose of combined treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03200847, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Oct 2024.