Clinical Trials /

Veliparib, Pembrolizumab, and Combination Chemotherapy in Treating Patient With Locally Advanced Rectal Cancer

NCT02921256

Description:

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.

Related Conditions:
  • Rectal Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Veliparib, Pembrolizumab, and Combination Chemotherapy in Treating Patient With Locally Advanced Rectal Cancer
  • Official Title: A Phase II Clinical Trial Platform of Sensitization Utilizing Total Neoadjuvant Therapy (TNT) in Rectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-00222
  • SECONDARY ID: NCI-2016-00222
  • SECONDARY ID: NRG-GI002
  • SECONDARY ID: s17-00197
  • SECONDARY ID: NRG-GI002
  • SECONDARY ID: NRG-GI002
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT02921256

Conditions

  • Rectal Adenocarcinoma
  • Stage II Rectal Cancer AJCC v7
  • Stage III Rectal Cancer AJCC v7

Interventions

DrugSynonymsArms
CapecitabineRo 09-1978/000, XelodaArm I (mFOLFOX6, RT, capecitabine)
Fluorouracil5 Fluorouracil, 5 Fluorouracilum, 5 FU, 5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-Fu, 5FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Arm I (mFOLFOX6, RT, capecitabine)
LeucovorinFolinic acidArm I (mFOLFOX6, RT, capecitabine)
Oxaliplatin1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669Arm I (mFOLFOX6, RT, capecitabine)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm III (mFOLFOX6, RT, capecitabine, pembrolizumab)
VeliparibABT-888, PARP-1 inhibitor ABT-888Arm II (mFOLFOX6, RT, capecitabine, veliparib)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To demonstrate an absolute improvement in neoadjuvant rectal cancer (NAR) score for the
      experimental regimen as compared to concurrently randomized control patients.

      SECONDARY OBJECTIVES:

      I. To compare overall survival (OS). II. To compare disease-free survival (DFS). III. To
      compare the rate of pathologic complete response (pCR) (nodes and tumor).

      IV. To compare the rate of sphincter preservation.

      TERTIARY OBJECTIVES:

      I. To compare the proportion of patients who have a tumor resection overall, conditional on
      beginning induction chemotherapy, and conditional on beginning chemoradiotherapy.

      II. To compare time from initiation of chemoradiotherapy to surgery in the subset of patients
      with tumor resection.

      EXPLORATORY OBJECTIVES:

      I. To estimate the rate of disease progression during chemotherapy (prior to chemoradiation).

      II. To compare the rate of clinical complete response rate (cCR). III. To compare the rate of
      negative circumferential margin. IV. To compare the rate of completion of all cycles of
      neoadjuvant chemotherapy.

      V. To compare the rate of completion of full course of chemoradiation. VI. To compare the
      toxicity and safety between interventions. VII. To explore the correlative molecular
      predictors of response and distant failure.

      VIII. To explore the relationship between radiographic findings and pathologic outcomes.

      OUTLINE: Patients are randomized to 1 of 3 treatment arms.

      ARM I: Patients receive mFOLFOX6 regimen consisting of oxaliplatin intravenously (IV) over 2
      hours, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over
      46-48 hours on days 1-2. Treatment repeats every 2 weeks for 8 cycles in the absence of
      disease progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient
      undergo radiation therapy (RT) and receive capecitabine orally (PO) twice daily (BID)
      Monday-Friday for 5 weeks in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive mFOLFOX6 regimen consisting of oxaliplatin IV over 2 hours,
      leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46-48
      hours on days 1-2. Treatment repeats every 2 weeks for 8 cycles in the absence of disease
      progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo
      RT and receive capecitabine PO BID and veliparib PO BID Monday-Friday for 5 weeks in the
      absence of disease progression or unacceptable toxicity.

      ARM III: Patients receive mFOLFOX6 regimen consisting of oxaliplatin IV over 2 hours,
      leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46-48
      hours on days 1-2. Treatment repeats every 2 weeks for 8 cycles in the absence of disease
      progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo
      RT and receive capecitabine PO BID Monday-Friday for 5 weeks. They also receive pembrolizumab
      IV over 30 minutes every 3 weeks beginning on day 1 of RT for up to 6 cycles in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and every 6 months
      for up to 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (mFOLFOX6, RT, capecitabine)Active ComparatorPatients receive mFOLFOX6 regimen consisting of oxaliplatin IV over 2 hours on day 1, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46-48 hours on days 1-2. Treatment repeats every 2 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo RT and receive capecitabine PO BID Monday-Friday for 5 weeks in the absence of disease progression or unacceptable toxicity.
  • Capecitabine
  • Fluorouracil
  • Leucovorin
  • Oxaliplatin
Arm II (mFOLFOX6, RT, capecitabine, veliparib)ExperimentalPatients receive mFOLFOX6 regimen consisting of oxaliplatin IV over 2 hours on day 1, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46-48 hours on days 1-2. Treatment repeats every 2 weeks for up to 8 cycles in the absence of disease progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo RT and receive capecitabine PO BID and veliparib PO BID Monday-Friday for 5 weeks in the absence of disease progression or unacceptable toxicity.
  • Capecitabine
  • Fluorouracil
  • Leucovorin
  • Oxaliplatin
  • Veliparib
Arm III (mFOLFOX6, RT, capecitabine, pembrolizumab)ExperimentalARM III: Patients receive mFOLFOX6 regimen consisting of oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46-48 hours on days 1-2. Treatment repeats every 2 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo RT and receive capecitabine PO BID Monday-Friday for 5 weeks. They also receive pembrolizumab IV over 30 minutes every 3 weeks beginning on day 1 of RT for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
  • Capecitabine
  • Fluorouracil
  • Leucovorin
  • Oxaliplatin
  • Pembrolizumab

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in neoadjuvant rectal cancer (NAR) score
Time Frame:Baseline to up to 3 years
Safety Issue:
Description:A linear regression model that controls for the stratification factors (cT-stage and cN-stage) will be used. Mean NAR scores along with standard errors and confidence intervals will be reported by treatment.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:Time from start of study treatment, assessed up to 3 years
Safety Issue:
Description:Analyzed using the stratified log rank test with strata cT-stage and cN-stage. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Cox regression models will be used to estimate hazard ratios and associated confidence intervals.
Measure:Disease free survival
Time Frame:Time from start of study treatment, assessed up to 3 years
Safety Issue:
Description:Analyzed using the stratified log rank test with strata cT-stage and cN-stage. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Cox regression models will be used to estimate hazard ratios and associated confidence intervals.
Measure:Rate of pathologic complete response (nodes and tumor) ypT0 and ypN0
Time Frame:Up to 3 years
Safety Issue:
Description:Analyzed by a logistic regression model that controls for the stratification factors (cT-stage and cN-stage). Observed proportions along with confidence intervals will be presented by treatment.
Measure:Rate of sphincter preservation
Time Frame:Up to 3 years
Safety Issue:
Description:Analyzed by a logistic regression model that controls for the stratification factors (cT-stage and cN-stage). Observed proportions along with confidence intervals will be presented by treatment.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 14, 2021