Veliparib, Pembrolizumab, and Combination Chemotherapy in Treating Patient With Locally Advanced Rectal Cancer
Condition: Rectal Adenocarcinoma; Stage II Rectal Cancer AJCC v7; Stage III Rectal Cancer AJCC v7
MeSH terms: Rectal Neoplasms
Intervention: Capecitabine; Fluorouracil; Intensity-Modulated Radiation Therapy; Leucovorin; Oxaliplatin; Pembrolizumab; Veliparib
Intervention description: Given PO; Given IV; Undergo intensity modulated radiation therapy; Given IV; Given IV; Given IV; Given PO
Intervention MeSH terms: Leucovorin; Pembrolizumab; Capecitabine; Fluorouracil; Oxaliplatin; Veliparib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 363.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well veliparib or pembrolizumab work with
      combination chemotherapy and radiation therapy in treating patients with rectal cancer that
      has spread from where it started to nearby tissue or lymph nodes (locally advanced).
      Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell
      growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's
      immune system attack the cancer, and may interfere with the ability of tumor cells to grow
      and spread. Drugs used in chemotherapy, such as modified (m)FOLFOX6 regimen, work in
      different ways to stop the growth of tumor cells, either by killing the cells, by stopping
      them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy
      x-rays to kill tumor cells and shrink tumors. Giving veliparib or pembrolizumab with
      combination chemotherapy and radiation therapy may kill more tumor cells, make the tumor
      smaller, and reduce the amount of normal tissue that needs to be removed.
    

Eligibility criteria:

        Inclusion Criteria:

          -  The patient must have signed and dated an Institutional Review Board (IRB)-approved
             consent form that conforms to federal and institutional guidelines

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

          -  Diagnosis of adenocarcinoma of the rectum with the major portion of the tumor intact;
             Note: prior to randomization, the investigator must specify and document each of the
             following:

               -  Distance of the lowest tumor margin from the anal verge; and

               -  Intent for sphincter sparing or non-sphincter sparing surgical resection
                  according to the primary surgeon; and

               -  The majority of the untreated tumor must be < 12 cm from the anal verge or below
                  the peritoneal reflection as determined by the treating surgeon

          -  The tumor must be clinically determined to be locally advanced stage II or stage III
             rectal cancer, and must also meet any ONE of the following criteria:

               -  Distal location (as defined by measurement on magnetic resonance imaging [MRI],
                  transrectal ultrasound [ERUS]/pelvic computed tomography [CT] [with IV contrast]
                  scan or palpable on digital rectal examination [DRE]): cT3-4 =< 5 cm from the
                  anal verge, any N

               -  Bulky: any cT4 or evidence that the tumor is adjacent to (defined as within 3 mm
                  of) the mesorectal fascia on MRI or ERUS/pelvic CT (with IV contrast) scan

               -  High risk for metastatic disease with 4 or more regional lymph nodes (cN2);
                  clinical nodal or "cN" status for eligibility includes the total number of nodes
                  (N2 = 4 or more) in the mesorectal and superior rectal stations measuring >= 1.0
                  cm in any axis on cross sectional or endoscopic imaging; Note: nodes must measure
                  1.0 cm or greater to be considered positive for this eligibility requirement

               -  Not a candidate for sphincter-sparing surgical resection prior to neoadjuvant
                  therapy (as planned by the primary surgeon)

                    -  Note: clinical stage of the primary tumor and nodes may be determined
                       locally by rectal endoscopic ultrasound or pelvic MRI (pelvic MRI is
                       strongly preferred); CT scan with IV contrast is acceptable provided there
                       is evidence of T4 and/or N2 disease

          -  Patients must have the ability to swallow and retain oral medication

          -  Absolute neutrophil count (ANC) must be >= 1200/mm^3 (within 28 days before
             randomization)

          -  Platelet count must be >= 100,000/mm^3 (within 28 days before randomization)

          -  Hemoglobin must be >= 10 g/dL (within 28 days before randomization)

          -  Total bilirubin must be =< ULN (upper limit of normal) for the lab unless the patient
             has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert's disease or similar
             syndrome involving slow conjugation of bilirubin (within 28 days before randomization)

          -  Alkaline phosphatase must be =< 3 x ULN for the lab (within 28 days before
             randomization)

          -  Aspartate aminotransferase (AST) must be =< 3 x ULN for the lab (within 28 days before
             randomization);

               -  Note: if alanine aminotransferase (ALT) is performed instead of AST (per
                  institution's standard practice), the ALT value must be =< 3 x ULN; if both were
                  performed, the AST must also be =< 3 x ULN; if AST and/or ALT is >= ULN but =< 3
                  x ULN, serologic testing for hepatitis B and C must be performed and results for
                  viral infection must be negative

          -  Serum creatinine =< ULN for the lab and measured or calculated creatinine clearance >
             60 mL/min (within 28 days before randomization)

          -  Serum potassium, magnesium, and calcium levels within 28 days before randomization
             must be within normal limits (WNL) for the lab

          -  International normalized ratio of prothrombin time (INR) within 28 days before
             randomization must be =< ULN for the lab; patients who are therapeutically treated
             with an agent such as warfarin may participate if they are on a stable dose and no
             underlying abnormality in coagulation parameters exists per medical history

          -  Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known
             human immunodeficiency virus (HIV) disease must:

               -  Have a cluster of differentiation (CD)4 count >= 200 cells/uL within 30 days
                  before beginning study therapy

               -  Be off all antiretroviral therapy (prophylaxis/treatment) more than 60 days
                  before beginning study therapy, and

               -  Have no evidence of opportunistic infections

          -  Pregnancy test (urine or serum beta-human chorionic gonadotropin [HCG]) done within 72
             hours before randomization must be negative (for women of childbearing potential
             only); if urine pregnancy results are positive or cannot be confirmed as negative, a
             serum pregnancy test will be required

        Exclusion Criteria:

          -  Rectal cancer histology other than adenocarcinoma (i.e., sarcoma, lymphoma, squamous
             cell carcinoma, mucosal melanoma, etc.)

          -  Definitive clinical or radiologic evidence of metastatic disease; required imaging
             studies must have been performed within 28 days prior to randomization; Note: Distant
             clinical staging to exclude patients with overt metastatic disease is determined by:

               -  Chest: CT scan (preferred); chest x-ray posterioranterior (PA) and lateral
                  (acceptable); or positron emission tomography (PET) scan (acceptable)

               -  Abdomen: CT scan with IV contrast (preferred); or MRI (acceptable)

               -  Pelvis: MRI (preferred) or CT scan with IV contrast (acceptable)

                    -  (It is recommended that the same imaging tests that are performed before
                       randomization be used at follow-up time points; Note: CT scans of the
                       abdomen and pelvis must be performed with IV contrast)

          -  History of prior invasive rectal malignancy, regardless of disease-free interval

          -  Cardiac disease that would preclude the use of any of the drugs included in the GI002
             treatment regimen; this includes but is not limited to:

               -  Clinically unstable cardiac disease, including unstable atrial fibrillation,
                  symptomatic bradycardia, unstable congestive heart failure, active myocardial
                  ischemia, or indwelling temporary pacemaker

               -  Ventricular tachycardia or supraventricular tachycardia that requires treatment
                  with class Ia antiarrhythmic drugs (e.g., quinidine, procainamide, disopyramide)
                  or class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide); use of
                  other antiarrhythmic drugs is permitted

               -  Second- or third-degree atrioventricular (AV) block unless treated with a
                  permanent pacemaker

               -  Complete left bundle branch block (LBBB)

               -  History of long QT syndrome

               -  Corrected QT (QTc) >= 450 ms

          -  Sensory or motor neuropathy >= grade 2

          -  History of, or any evidence of active, non-infectious pneumonitis

          -  Active inflammatory bowel disease (i.e., patients requiring current medical
             interventions or who are symptomatic) or have a history of abdominal surgery or other
             medical condition that may, in the opinion of the treating physician, interfere with
             gastrointestinal motility or absorption

          -  Active autoimmune disease that has required systemic treatment within the past 2 years
             (i.e., with use of 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

          -  History of active TB (Bacillus tuberculosis)

          -  Active or chronic infection requiring systemic therapy

          -  Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form
             of immunosuppressive therapy within 7 days prior to the first dose of study therapy;
             the use of physiologic doses of corticosteroids may be approved after consultation
             with the study principal investigator (PI)

          -  Active seizure disorder uncontrolled by medication

          -  Any antineoplastic therapy for this cancer before randomization

          -  Synchronous colon cancer

          -  Other invasive cancer within 5 years before randomization; exceptions are colonic
             polyps, non-melanoma skin cancer or carcinoma-in-situ of the cervix

          -  Antineoplastic therapy (e.g. chemotherapy or targeted therapy) for other invasive
             cancer within 5 years before randomization; (for the purposes of this study, hormonal
             therapy is not considered chemotherapy)

          -  Prior treatment with an investigational compound being tested in this study (e.g.,
             poly ADP ribose polymerase [PARP] inhibitor, anti-PD-1, anti-PD-L1, or anti-PD-L2)

          -  Receipt of live vaccination within 28 days before randomization; seasonal flu vaccines
             that do not contain live virus are permitted

          -  Major surgery within 4 weeks before randomization

          -  Any therapeutic pelvic radiation

          -  Known homozygous DPD (dihydro pyrimidine dehydrogenase) deficiency

          -  Any of the following because this study involves agents that have known or potential
             genotoxic or mutagenic, and teratogenic effects:

               -  Pregnant women

               -  Nursing women who are unwilling to discontinue nursing

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception (e.g., hormonal or barrier method of birth control; abstinence) for
                  the duration of study treatment and for 4 months after the last dose of study
                  therapy

          -  Co-morbid illnesses or other concurrent disease that, in the judgement of the
             clinician obtaining informed consent, 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 or prevent required follow-up