RADVAX: A Stratified Phase I Trial of Pembrolizumab With Hypofractionated Radiotherapy in Patients With Advanced and Metastatic Cancers

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.