The purpose of this study is to evaluate the safety, tolerability and efficacy of doxorubicin
in combination with pembrolizumab in subjects with metastatic or unresectable soft tissue
sarcoma. Based on previous studies, pembrolizumab may be an effective study treatment.
The primary objective of this study is to assess the safety and toxicity profile of
doxorubicin and pembrolizumab in previously treated or untreated subjects with unresectable
or metastatic soft tissue sarcoma. The secondary objectives are to assess overall survival,
and response rate, duration of response, and progression-free survival (PFS) with this
regimen using RECIST 1.1 criteria. The exploratory objectives are to assess PFS, overall
response rate, duration of response, and disease control rate using the immune-related RECIST
(irRECIST) criteria, evaluate the correlation between PD-L1 expression levels and antitumor
activity of MK-3475, investigate other biomarkers that may correlate with tumor responses,
and evaluate differences in tumor tissue characteristics in biopsies taken during or
post-treatment with MK-3475 versus baseline.
1. Be willing and able to provide written informed consent for the trial.
2. Must have a histologically confirmed diagnosis of unresectable or metastatic soft
tissue sarcoma not amenable to curative treatment with surgery or radiotherapy.
Patients with Ewings sarcoma, osteosarcoma, chondrosarcoma, Kaposis sarcoma,
gastrointestinal stromal tumors (GIST), clear cell sarcoma, alveolar soft part sarcoma
and any other soft tissue or bone sarcoma felt to be chemotherapy resistant in the
opinion of the Sponsor-Investigator will be excluded.
3. Must not have received prior treatment with an anthracycline chemotherapy (eg,
doxorubicin) and/or anti-PD-1/PD-L1 therapy.
4. May have had any number of prior systemic cytotoxic therapies for
5. Must have at least one radiologically measurable lesion as per RECIST 1.1 defined as a
lesion that is 10mm in longest diameter or lymph node that is 15mm in short axis
imaged by CT scan or MRI. Tumors with previously irradiated field will be designated
as nontarget lesions unless progression is documented or a biopsy is obtained to
confirm persistence of at least 90 days following completion of radiotherapy.
6. All subjects with accessible tumor will be asked to provide a fresh tumor biopsy if
they can be safely biopsied in the opinion of the investigator. Recently obtained
archived core or excisional biopsy of a tumor lesion (obtained up to 12 months prior
to Cycle 1 Day 1) may be substituted only if the subject is unwilling or unable (e.g.
inaccessible or subject safety concern) to undergo a fresh tumor biopsy. Subjects who
are unwilling or unable to have a fresh tumor biopsy and do not have recently obtained
archived tissue available may submit an archived specimen (obtained > 12 months prior
to Cycle 1 Day 1) only upon approval from the Sponsor-Investigator.
7. Be at least 12 years of age on day of signing informed consent. Assent will be
obtained in appropriately aged subjects per institutional guidelines.
8. ECOG performance status 0 or 1.
9. Life expectancy of at least 3 months per the Investigator.
10. Have adequate organ function as indicated by the laboratory values in Table 1 of
protocol. All screening labs should be performed within 10 days of treatment
initiation. PT/INR and PTT must be performed within 7 days of study treatment
initiation for subjects on anti-coagulants such as coumadin/heparin.
11. The subject has left ventricular ejection fraction (LVEF) greater than or equal to 50%
assessed within 21 days prior to study regimen initiation.
12. Subjects must not be expecting to conceive or father children within the timeframe
referenced below. Subjects of childbearing potential must be willing to adhere to the
contraception requirement as described in Section 3.3.2 from the day of the screening
visit (or 14 days prior to the initiation of study treatment for oral contraception)
throughout the study period up to 120 days after the last dose of pembrolizumab and/or
up to 180 days after the last dose of doxorubicin. If there is any question that a
subject of childbearing potential will not reliably comply with the requirements for
contraception, that subject should not be entered into the study.
13. Female subjects of childbearing potential must have a negative urine or serum
pregnancy test at screening (within 72 hours of first dose of study treatment). If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required. The serum pregnancy test must be negative for the subject to be eligible.
14. Subject has voluntarily agreed to participate by giving written informed consent for
the trial. The subject may also provide consent for Optional and Future
Studies-Biospecimen Collection. However, the subject may participate in the main trial
without participating in Optional and Future Studies.
1. Currently participating and receiving study therapy or have participated in a study of
an investigational agent and received study therapy or used an investigational device
within 30 days of the first dose of study regimen.
2. Have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of study
3. Have a known history of active TB (Bacillus Tuberculosis).
4. Have had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the
first dose of study regimen or have not recovered (i.e. less than or equal to Grade 1
or at baseline) from adverse events due to previous mAbs.
5. Have had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to the first dose of study regimen or who have not recovered
(i.e. less than or equal to Grade 1 or at baseline) from adverse events due to
previous chemotherapy, targeted small molecule therapy, or radiation therapy.
Note: Subjects with less than or equal to Grade 2 neuropathy are an exception to this
criterion and may qualify for the study.
Note: If subjects have received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting therapy
as determined by the Investigator.
6. Have 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.
7. Have 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 study regimen 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 the first dose of the study regimen. This
exception does not include carcinomatous meningitis which is excluded regardless of
8. Have 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. Have known history of, or any evidence of active, non-infectious pneumonitis.
10. Have an active infection requiring systemic therapy (uncomplicated urinary tract
infection treated with oral antibiotics is permitted).
11. Have a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the subjects
participation for the full duration of the trial, or is not in the best interest of
the subjects to participate, in the opinion of the treating Investigator.
12. Have known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial as determined by the Investigator.
13. Are pregnant or breastfeeding
14. Have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
15. Have a known history of Human Immunodeficiency Virus infection (e.g. HIV 1/2
16. Have known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA
[qualitative] is detected).
17. Have 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.