Study of Pembrolizumab and Concurrent Radiation in Patients With Previously Treated Carcinoma of Unknown Primary
Condition: Carcinoma, Unspecified Site
MeSH terms: Carcinoma
Intervention: Pembrolizumab; External Beam Radiation Therapy
Intervention description: 200mg IV at day -21, then day 1 of each 21-day cycle for a maximum of 24 continuous months of Pembrolizumab (35 cycles) from Cycle 1 Day 1 (C1D1) can be administered.; 20-30 Gy over five fractions for up to two cycles.
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Single-arm phase 2 study to examine pembrolizumab and concurrent radiation to induce an
      abscopal effect in patients with previously treated carcinoma of unknown primary (CUP16-268)
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization for release of personal health
             information prior to registration. NOTE: HIPAA authorization may be included in the
             informed consent or obtained separately.

          -  Age ≥ 18 years at the time of consent.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 within 28 days
             prior to registration.

          -  Archival tissue must be available and identified during screening and shipped prior to
             Day -21. If archival tissue is not available and the subject is not undergoing a
             standard of care biopsy, the subject must undergo a research biopsy to obtain fresh
             tissue prior to start of treatment.

          -  Carcinoma of unknown primary after the following diagnostic procedures have been
             performed if clinically indicated and are unrevealing of the primary site:

               -  Complete history and clinically appropriate physical

               -  CT scan of chest, abdomen, and pelvis

               -  Directed evaluation of symptomatic areas

               -  Mammogram in women

               -  Colonoscopy in patients with liver metastasis or an elevated CEA

               -  Direct pathologic comparison with prior tumor specimens, where possible, even if
                  prior tumor is early-stage or clinically remote from current disease NOTE:
                  Immunohistochemical stains will be performed according to institutional
                  standards. If a primary carcinoma is identified, the patient should undergo
                  treatment as appropriate for that primary tumor and not be enrolled in the study.
                  The above diagnostic workup does not need to be performed if: (1) it was
                  previously completed at the time of original diagnosis or (2) the investigator
                  does not believe the workup has clinical utility at the current time, given that
                  the patient has received interval therapy.

          -  Histologic confirmation of metastatic adenocarcinoma, poorly differentiated non-small
             cell carcinoma, or poorly differentiated squamous carcinoma. NOTE: Pathology
             consultation at Mayo Clinic is recommended if clinically indicated. One scenario is
             where unknown primary is the most likely diagnosis but immunostains show relatively
             site-specific marker staining (e.g., CD45, TTF1, chromogranin, GATA3, PAX8, PSA,
             melanocytic markers). Information provided for pathology consultation should include
             recent H&P and imaging reports.

          -  If and when available, submission of genomic sequencing and expression profiling
             results is mandatory. Results of testing are not required prior to treatment.

          -  At least one measurable lesion (per RECIST 1.1) outside the planned RT fields.

          -  Stable or progressive disease after, or was unable to tolerate, at least one line of
             prior anticancer therapy for this disease. NOTE: For patients with stable disease, it
             is strongly encouraged to confirm the presence of active disease (eg, demonstrating
             18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (FDG) avidity via PET or repeat
             biopsy).

          -  Radiation oncology consultation at enrolling site ≤ 56 days prior to registration to
             confirm at least two metastatic lesions which are targetable by RT at doses and
             schedule prescribed in this study and which reside in non-overlapping RT fields.

          -  Demonstrate adequate organ function as defined in the table below. All screening labs
             to be obtained within 28 days prior to registration.

               -  Hematological

                    -  Absolute Neutrophil Count (ANC) ≥ 900 K/mm3

                    -  Hemoglobin (Hgb) ≥ 8.5 g/dL without transfusion or EPO dependency (≤ 7 days
                       prior to assessment)

                    -  Platelets ≥ 90,000 / mcL

               -  Renal

                  ---Creatinine 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

               -  Hepatic

                    -  Bilirubin Total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects
                       with total bilirubin levels > 1.5 ULN OR total bilirubin ≤2 X ULN if liver
                       metastases are present

                    -  Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 X
                       ULN OR ≤ 5 X ULN for subjects with liver metastases

                    -  Albumin > 2.5 g/dL

          -  Females of childbearing potential must have a negative serum pregnancy test within 72
             hours prior to registration. NOTE: If the urine test is positive or cannot be
             confirmed as negative, a serum pregnancy test will be required. NOTE: breast milk
             cannot be stored for future use while the mother is being treated on study

          -  Females of childbearing potential and males must be willing to abstain from
             heterosexual activity (abstinence) or use effective methods of contraception as
             described in the protocol from the time of informed consent until 120 days after
             treatment discontinuation. NOTE: Females are considered of child bearing potential
             unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal
             ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least
             12 consecutive months

          -  Willingness to return to the enrolling institution for follow up

          -  Willingness to provide tissue and blood samples for correlative research purposes

        Exclusion Criteria:

          -  Prior radiation to an area of the body which, if included in the current radiation
             field, poses an unacceptably high risk of toxicity in the opinion of the investigator.
             NOTE: A prior field that overlaps with the current field, by itself, does not exclude
             the patient.

          -  Any of the following

             --Melanoma. NOTE: Positive tumor staining for S-100 or HMB45 alone does not exclude
             patients.

             ---If immunostains are performed, and any of the below tests are positive:

               -  Hematologic CD45+ (others such as CD2, CD20, CD30, CD43 also suggest hematologic
                  origin)

               -  Lung or thyroid origin (Thyroid Transcription Factor [TTF-1]). NOTE: Patients
                  with biopsy proven TTF-1 positive tumor who do not have clinical evidence for
                  either lung or thyroid cancer (e.g. a dominant lung mass) are still eligible.

          -  Progressed on 4 or more lines of prior chemotherapy for this cancer. NOTE:
             Bisphosphonates and neoadjuvant/adjuvant anticancer therapies (including locally
             directed therapies) do not count as a line of therapy with regard to this exclusion
             criteria.

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens.

          -  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 received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  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. NOTE: Inhaled steroids or steroid injections for joint
             disease are allowed.

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

          -  Prior severe allergic reactions to a monoclonal antibody or 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
             due to agents administered more than 4 weeks earlier.

          -  Other active malignancy which requires current treatment and which in the opinion of
             the site investigator is likely to interfere with evaluation of disease assessment.

             --NOTE: Continuation of hormonal therapies is allowed.

          -  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.

          -  Major surgery ≤ 4 weeks from registration. NOTE: Diagnostic laparoscopy (without other
             intervention) and/or biopsies (needle aspirate, core biopsy, open biopsy, etc…) are
             not considered major surgery. If subject received surgery, they must have recovered
             adequately from the toxicity and/or complications from the intervention prior to
             starting therapy.

          -  Uncontrolled intercurrent illness which in the opinion of the investigator poses
             unacceptably high risk when combined with study treatment, including but not limited
             to the following:

               -  Symptomatic congestive heart failure

               -  Unstable angina pectoris

               -  Severely impaired lung function

               -  Known history of active TB (Bacillus Tuberculosis)

               -  Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

                  ---(NOTE: Optimal glycemic control should be achieved before starting trial
                  therapy.)

               -  Significant underlying liver disease such as cirrhosis or severe hepatic
                  impairment

               -  Has known psychiatric or substance abuse disorders that would interfere with
                  cooperation with the requirements of the trial.

          -  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.

          -  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.

          -  For patients in whom planned RT fields will include the heart, any of the following
             heart conditions, if in the opinion of the investigator they pose unacceptably high
             risk when combined with study treatment:

               -  Prior symptomatic congestive heart failure

               -  Documented myocardial infarction ≤6 months prior to registration (pretreatment
                  ECG evidence of infarct only will not exclude patients)

               -  Prior significant ventricular arrhythmia requiring medication

               -  Prior 2nd or 3rd degree heart block or other types of clinically significant
                  conduction delay ≤ 6 months prior to registration

               -  Clinically significant pericardial disease (including pericardial effusion,
                  pericarditis) or cardiac valvular disease ≤12 months prior to registration NOTE:
                  As part of history and physical, all patients must be assessed for signs or
                  symptoms of cardiac disease, or for prior history of cardiac disease. These
                  conditions include but are not limited to diseases related to cardiac valves,
                  pericardium, myocardium, atrioventricular delays or arrhythmias. It is strongly
                  recommended that signs or symptoms of potentially clinically significant disease
                  be evaluated with comprehensive cardiac echo.

          -  For patients in whom planned RT fields during the study will include the chest, any of
             the following, if in the opinion of the site investigator they pose unacceptably high
             risk when combined with study treatment:

               -  Prior fistula within thorax, including bronchoalveolar or esophageal.

               -  Respiratory condition that required oxygen supplementation ≤ 3 months prior to
                  registration

               -  Clinically significant pulmonary hypertension ≤ 12 months prior to registration

               -  Pneumonia requiring treatment ≤ 1 month prior to registration

               -  Pulmonary embolism requiring treatment ≤ 6 months prior to registration

               -  Pleural effusion requiring drainage ≤ 12 months prior to registration

          -  Has known history of, or any evidence of active, non-infectious pneumonitis

          -  Currently uncontrolled hyper/hypothyroidism or hyper/hypocortisolism if in the opinion
             of the investigator they pose unacceptably high risk when combined with study
             treatment

          -  Received live vaccine ≤ 30 days prior to registration. 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.

          -  History of organ or stem cell transplantation