RADVAX: A Stratified Phase I Trial of Pembrolizumab With Hypofractionated Radiotherapy in Patients With Advanced and Metastatic Cancers
Condition: Metastatic Cancers
MeSH terms: Neoplasm Metastasis; Neoplasms; Neoplasms, Second Primary
Intervention: Pembrolizumab; Radiotherapy
Intervention MeSH terms: Pembrolizumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 59.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Phase I clinical trial of hypofractionated radiotherapy to an isolated index lesion in
      combination with the PD-1 inhibitor, Pembrolizumab in patients with metastatic cancers who
      have failed anti-PD-1 therapy (melanoma and NSCLC) and patients with metastatic cancers who
      have have progressed after at least one regimen of systemic therapy (breast, pancreas, and
      other).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent/assent for the trial.

          -  Be 18 years of age on day of signing informed consent.

          -  Histologically confirmed diagnosis of cancer as per the cohort specifications

          -  Stage IV cancer by AJCC staging criteria (except for pancreatic cancer cohort)

          -  Locally advanced or metastatic pancreatic cancer for the pancreatic cancer cohort

          -  Progression of disease while on anti-PD-1 or anti-PD-L1 therapy for melanoma and NSCLC
             patients. For this group, patients must met the following criteria:

               1. Received at least 2 doses of an anti-PD1 or anti-PD-L1 therapy

               2. Had progressive disease documented radiologically by RECIST v1.1 criteria.

          -  Progression or refractory disease to at least one regimen of therapy for metastatic
             disease in the breast and pancreatic cancer cohorts

          -  Presence of an index lesion > 1 cm amenable to hypofractionated radiotherapy

          -  Patients who have metastatic cancer must have at least one lesion that is outside the
             radiation field that measures greater than one cm that can be followed by RECIST 1.1.
             This lesion, if it is close to the radiated lesion, must receive no more than 10% of
             the dose prescribed to the target lesion.

          -  Have provided tissue from an archival tissue sample or newly obtained core or
             excisional biopsy of a tumor lesion.

          -  Have a performance status of 0 or 1 on the ECOG Performance Scale.

          -  Ability to tolerate hypofractionated radiation therapy (e.g. lie flat and hold
             position)

          -  Demonstrate adequate organ function , all screening labs should be performed within 14
             days of treatment initiation.

          -  Adequate Organ Function Laboratory Values System Laboratory Value Hematological
             Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥9
             g/dL or ≥5.6 mmol/L Renal Serum creatinine OR Measured or calculateda creatinine
             clearance (GFR can also be used in place of creatinine or CrCl)

               -  1.5 X upper limit of normal (ULN) OR

                  ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN 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 Creatinine clearance should be
                  calculated per institutional standard

          -  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.

          -  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.

        Exclusion Criteria

          -  The subject must be excluded from participating in the trial if the subject:

          -  Is currently participating in or has participated in a study of an investigational
             agent or using 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. Systemic steroids administered specifically as a premedication for
             chemotherapy infusion or radiotherapy are allowed.

          -  Has had a prior monoclonal antibody 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.

          -  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 therapy.

          -  A history of prior radiotherapy that precludes delivery of hypofractionated
             radiotherapy

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy.

          -  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.

          -  Has an active automimmune disease requiring systemic treatment within the past 3
             months or a documented history of clinically severe autoimmune disease, or a syndrome
             that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or
             resolved childhood asthma/atopy would be an exception to this rule. Subjects that
             require intermittent use of bronchodilators or local steroid injections would not be
             excluded from the study. Subjects with hypothyroidism stable on hormone replacement or
             Sjogren's syndrome will not be excluded from the study.

          -  Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

          -  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 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 prior to the first dose of trial treatment.