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Pembrolizumab and All-Trans Retinoic Acid Combination Treatment of Advanced Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03200847
Recruitment Status : Recruiting
First Posted : June 27, 2017
Last Update Posted : July 1, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University of Colorado, Denver

Brief Summary:
This is a Phase I/Ib investigator-initiated open label of the combination of VESANOID and pembrolizumab treatment.

Condition or disease Intervention/treatment Phase
Stage IV Melanoma Stage III Melanoma Advanced Melanoma Drug: Pembrolizumab with All-Trans Retinoic Acid Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pembrolizumab and All-Trans Retinoic Acid in Combination Treatment of Advanced Melanoma
Actual Study Start Date : October 31, 2017
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: 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).
Drug: 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
Other Names:
  • VESANOID
  • Keytruda




Primary Outcome Measures :
  1. Maximally Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of the combination of pembrolizumab and All-Trans Retinoic Acid [ Time Frame: 5 years ]
    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.


Secondary Outcome Measures :
  1. Dose-Limiting Toxicity (DLT) for the combined treatment of pembrolizumab and All-Trans Retinoic Acid for each patient [ Time Frame: 5 years ]
    Toxicity will be evaluated according to NCI CTCAE Version 4.0. A dose limiting toxicity (DLT) will be defined as any grade 3 or higher related to VESNOID and/or Pembrolizumab.


Other Outcome Measures:
  1. The anti-tumor activity for each patient [ Time Frame: 5 years ]
    Anti-tumor activity will be determined by the reduction in MD (immunosuppressive myeloid-derived suppressor cells) frequency and suppressive function (measured as a continuous variable) in peripheral blood of advanced melanoma patients undergoing the combined treatment of pembrolizumab and All-Trans Retinoic Acid



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03200847


Contacts
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Contact: Christine Christensen 720-848-0592 christine.christensen@ucdenver.edu

Locations
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United States, Colorado
University of Colorado Denver Recruiting
Aurora, Colorado, United States, 80045
Contact: Christine Christensen    720-848-0592    christine.christensen@ucdenver.edu   
Principal Investigator: Martin McCarter, MD         
Poudre Valley Hospital Not yet recruiting
Fort Collins, Colorado, United States, 80528
Contact: Valerie Cummins    970-297-6159    valerie.cummins@uchealth.org   
Principal Investigator: Steven Schuster, MD         
Sponsors and Collaborators
University of Colorado, Denver
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Martin McCarter, MD University of Colorado, Denver

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Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT03200847    
Other Study ID Numbers: 16-1080.cc
First Posted: June 27, 2017    Key Record Dates
Last Update Posted: July 1, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University of Colorado, Denver:
Pembrolizumab
All-Trans Retinoic Acid
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Tretinoin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Keratolytic Agents
Dermatologic Agents