To determine the irRECIST* response rate of pembrolizumab with ipilimumab following initial
progression or stable disease to anti-PD1/L1 antibody (or combination not containing
anti-CTLA4) in subjects with advanced melanoma.
1. To summarize the progression-free survival (RECIST v1.1 and irRC) of the combination
following prior treatment with anti-PD1/L1 antibody.
2. To assess the safety of the combination following prior treatment with anti-PD1/L1
To evaluate changes in the tumor microenvironment and other biospecimens before and after
adding ipilimumab to pembrolizumab.
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial.
2. Be 18 years of age on day of signing informed consent.
3. Have experienced disease progression or stable disease lasting at least 24 weeks
during treatment with an anti-PD1/L1 antibody as the treatment regimen immediately
prior to accrual to this study or disease progression within 6 months of adjuvant
4. Have measurable disease based on irRECIST 1.1.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
6. Demonstrate adequate organ function as defined below, all screening labs should be
performed within 10 days of treatment initiation.
Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL
Hemoglobin ≥8 g/dL or ≥4.96 mmol/L
Renal Serum creatinine OR Measured or calculated creatinine clearance ≤1.5 X upper
limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X
institutional ULN (GFR can also be used in place of creatinine or CrCl)
Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with
total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN
for subjects with liver metastases Albumin >2.5 mg/dL
Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN
unless subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants
Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
7. 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.
8. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year.
9. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy.
The subject must be excluded from participating in the trial if the subject:
1. Has received study therapy (including investigational device) as part of a clinical
trial within 4 weeks of the first dose of treatment, with the exclusion of an
anti-PD1/L1 antibody given as either a single agent or non-CTLA-4 antibody containing
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
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 (excluding commercial or investigational anti-PD1 or anti-PD-L1 antibodies as
single agents) 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.
- 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
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 known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.
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.
10. Patients with uveal/ocular melanoma are excluded.
11. Has known history of, or any evidence of active, non-infectious pneumonitis.
12. Has an active infection requiring systemic therapy.
13. 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.
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 trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
16. Has received prior therapy with an anti-CTLA4 agent.
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
19. 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 are live attenuated vaccines, and are