Pembrolizumab in Subjects With Incurable Platinum-Refractory Germ Cell Tumors
Condition: Germ Cell Neoplasms; Testicular Neoplasms; Non Seminomatous Germ Cell Tumors; Mediastinal Neoplasms; Genital Neoplasms, Male; Genital Neoplasms, Female; Ovarian Neoplasms
MeSH terms: Neoplasms; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Testicular Neoplasms; Genital Neoplasms, Male; Genital Neoplasms, Female; Mediastinal Neoplasms
Intervention: Pembrolizumab
Intervention description: 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or after 52 weeks of therapy.
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pembrolizumab; MK-3475; PMNSGCT; PD-L1; Non Seminomatous Germ Cell Tumors

Summary:

      This is an open label, multi-institutional, single arm phase II trial of pembrolizumab in
      patients with incurable platinum refractory germ cell tumors. No randomization or blinding is
      involved.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization for release of personal health
             information. NOTE: HIPAA authorization may be included in the informed consent or
             obtained separately.

          -  Age ≥ 18 years at the time of consent.

          -  ECOG Performance Status of 0 or 1 within 14 days prior to registration for protocol
             therapy.

          -  Subjects must have histological or serological proof of metastatic germ cell neoplasm
             (gonadal or extragonadal primary) with disease not amenable to cure with either
             surgery or chemotherapy. Subjects with seminoma and non-seminoma are eligible, as are
             women with ovarian GCTs.

          -  Subjects must have evidence of recurrent or metastatic carcinoma by one or more of the
             following: the appearance of metastatic disease on chest x-ray or CT scan, or the
             appearance of rising tumor marker: AFP or beta-HCG. NOTE: If a rising tumor marker is
             the only evidence of progressive disease, at least 2 consecutive rising values at
             least one week apart are needed. Subjects with only evidence of disease as rising
             tumor marker AFP and beta-HCG will be provided alternate causes of increased serum
             levels of these markers are not present, such as cross reaction with luteinizing
             hormone (LH) (that can be tested if needed by testosterone suppression of LH),
             hepatitis, use of marijuana, or second primary tumor, etc.

          -  Subjects must have received initial cisplatin based combination therapy, such as
             bleomycin-etoposide-cisplatin (BEP), cisplatin-etoposide (EP),
             etoposide-ifosfamide-cisplatin (VIP), or similar regimens AND demonstrated progression
             following the administration of at least one 'salvage' regimen for advanced germ cell
             neoplasm, such as high dose chemotherapy, paclitaxel-ifosfamide-cisplatin (TIP), or
             vinblastine-ifosfamide-cisplatin (VeIP).

          -  "Failure" of prior therapy is defined as: a >25% increase in the products of
             perpendicular diameters of measurable tumor masses during prior therapy which are not
             amenable to surgical resection; the presence of new tumors which are not amenable to
             surgical resection; an increase in AFP or beta-hCG (two separate determinations at
             least one week apart are required if rising tumor markers are the only evidence of
             failure). NOTE: Subjects with clinically growing "teratoma" (normal declining tumor
             markers and radiographic or clinical progression) should be considered for surgery.

          -  Subjects are eligible after first line platinum based chemotherapy if their disease
             has relapsed and they have Primary Mediastinal Non Seminomatous Germ Cell tumor
             (PMNSGCT) or late relapse (> 2 years) not amenable to surgical resection.

          -  Subjects must be willing to provide tissue from a newly obtained core or excisional
             biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6
             weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom
             newly-obtained samples cannot be provided (e.g., inaccessible or subject safety
             concern) may submit an archived specimen only upon agreement from the sponsor
             investigator

          -  Female subjects 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 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.

          -  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.

          -  Measurable disease according to RECIST v1.1 obtained by imaging within 28 days prior
             to registration.

        Exclusion Criteria:

          -  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
             (AE) 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. NOTE 1: Subjects
             with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the
             study. NOTE 2: 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 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.

          -  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.

          -  Presence of interstitial lung disease or history of pneumonitis requiring treatment
             with corticosteroids.

          -  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 PD-1, PD-L1, or CTLA-4 inhibitors.

          -  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.