Inclusion Criteria:
1. Male/female participants who are at least 18 years of age on the day of signing
informed consent with histologically confirmed diagnosis of acral or mucosal melanoma
with stage IV or unresectable stage III diseasewill be enrolled in this study.
2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
1.Evaluation of ECOG is to be performed within 7 days prior to the first dose of study
intervention. 3. Have progressed after at least one line of therapy which must include anti-PD-1
(and/or anti-CTLA4) treatment for metastatic melanoma.
1. patients with actionable BRAF mutation must also have been treated with
appropriate targeted therapy (BRAF inhibitor and/or RAF inhibitor),
2. patient treated with chemotherapy can be enrolled. 4. Participants must have progressed on treatment with an anti-PD-1/L1 mAb administered
either as monotherapy or in combination with other checkpoint inhibitors or other
therapies. PD-1 treatment progression is defined by meeting all of the following
criteria:
1. Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
2. Has demonstrated disease progression after anti-PD-1/L1 as defined by RECIST
v1.1.
5. c. Progressive disease has been documented within 12 weeks from the last dose of
anti-PD-1/L1 mAb. Patients must be able to swallow tablets and absorb vactosertib.
6. Life expectancy > 3 months. 7. Patients with CNS metastasis must have stable neurologic function without evidence of
CNS progression within 8 weeks (i.e., patients with controlled, asymptomatic or with
resected CNS metastases with no radiological evidence of disease)
8. Have measurable disease based on RECIST 1.1. Lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated in such
lesions.
9. Male participants:
A male participant must agree to use a contraception as detailed in Appendix 3 of this
protocol during the treatment period and for at least [120 days, corresponding to time
needed to eliminate any study treatment(s) (e.g. 5 terminal half-lives for pembrolizumab
and/or any active comparator/combination) plus an additional 90 days (a spermatogenesis
cycle) for study treatments with evidence of genotoxicity at any dose] after the last dose
of study treatment and refrain from donating sperm during this period.
Female participants:
A male participant must agree to use a contraception as detailed in Appendix 3 of this
protocol during the treatment period and for at least 120 days 10. A female participant is
eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at
least one of the following conditions applies: 4. Not a woman of childbearing potential
(WOCBP) as defined in Appendix 3 OR b. A WOCBP who agrees to follow the contraceptive
guidance in Appendix 3 during the treatment period and for at least 120 days (corresponding
to time needed to eliminate any study treatments (pembrolizumab and vactosertib) plus 30
days (a menstruation cycle) for study treatments with risk of genotoxicity after the last
dose of study treatment.
11. The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
12. Have adequate organ function as defined as following. Specimens must be collected
within 10 days prior to the start of study intervention.
- - Absolute neutrophil count (ANC)≥1500/µL.
- - Hemoglobin≥9.0 g/dL or ≥5.6 mmol/La.
- - Creatinine OR Measured or calculatedb creatinine clearance(GFR can also be used in
place of creatinine or CrCl)≤1.5 × ULN OR.
≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN.
- - Total bilirubin≤1.5 ×ULN (≤3 × ULN for participants with liver metastases) OR direct
bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN.
- - AST (SGOT) and ALT (SGPT)≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
- International normalized ratio (INR) OR prothrombin time (PT), Activated partial
thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant
therapy as long as PT or aPTT is within therapeutic range of intended use of
anticoagulants.
Exclusion Criteria:
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to
[randomization/allocation] (see Appendix 3). If the urine test is positive or cannot
be confirmed as negative, a serum pregnancy test will be required.
2. Has received prior radiotherapy within 2 weeks of start of study intervention.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
3. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the
first dose of study drug. Administration of killed vaccines is allowed.
4. Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study intervention.
5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
6. Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years. Participants with basal cell carcinoma of the skin, squamous
cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the
bladder, that have undergone potentially curative therapy are not excluded.
7. Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and without requirement of steroid treatment for at least 14 days prior to
first dose of study intervention.
8. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
9. 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 (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.
10. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required
steroids or has current pneumonitis/interstitial lung disease.
11. Has an active infection requiring systemic therapy.
12. Concurrent active Hepatitis B (defined as HBsAG positive and/or detectable HBV DNA)
and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA)
infection. Note: no testing for Hepatitis B and Hepatitis C is required unless
mandated by local health authority.
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality
or other circumstance that might confound the results of the study, interfere with the
participant's participation for the full duration of the study, such that it is not in
the best interest of the participant to participate, in the opinion of the treating
investigator.
14. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
15. Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.
16. Has had an allogenic tissue/solid organ transplant.
17. Patients treated with co-administration of a strong CYP3A4 inducers (e.g. rifampin,
phenytoin, carbamazepine, phenobarbital, and St. John's Wort) or inhibitors (e.g.
clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole,
telithromycin, and voriconazole)
18. Demonstrates a QTc interval >450 ms for men or >470 ms for women, or has known history
of congenital QT-prolongation or Torsade de pointes (TdP).
