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. Monoclonal antibodies, such as pembrolizumab, 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:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Veliparib 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-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Arm I (mFOLFOX6, RT, capecitabine)
Leucovorin CalciumAdinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, citrovorum factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, WellcovorinArm 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)
VeliparibABT-888, PARP-1 inhibitor ABT-888Arm II (mFOLFOX6, RT, capecitabine, veliparib)

Purpose

This randomized phase II trial studies how well veliparib works 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. 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 with combination chemotherapy and radiation therapy may kill more tumor cells and giving it before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed Description

      PRIMARY OBJECTIVES:

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

      SECONDARY OBJECTIVES:

      I. To compare overall survival (OS). II. To compare disease-free survival (DFS). III. To
      estimate the rate of disease progression during chemotherapy (prior to chemoradiation).

      IV. To compare the rate of pathologic complete response (nodes and tumor). V. To compare the
      rate of clinical complete response rate (cCR). VI. To compare the rate of negative
      circumferential margin. VII. To compare the rate of completion of all cycles of neoadjuvant
      chemotherapy.

      VIII. To compare the rate of completion of full course of chemoradiation. IX. To compare the
      rate of sphincter preservation. X. To compare the toxicity and safety between interventions.
      XI. To explore the correlative molecular predictors of response and distant failure.

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

      OUTLINE: Patients are randomized to 1 of 2 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 courses in the absence of
      disease progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient
      undergo radiation therapy 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 courses in the absence of disease
      progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo
      radiation therapy and receive capecitabine PO BID and veliparib PO BID Monday-Friday for 5
      weeks 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 courses in the absence of disease progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo radiation therapy and receive capecitabine PO BID Monday-Friday for 5 weeks in the absence of disease progression or unacceptable toxicity.
  • Capecitabine
  • Fluorouracil
  • Leucovorin Calcium
  • 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 courses in the absence of disease progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo radiation therapy and receive capecitabine PO BID and veliparib PO BID Monday-Friday for 5 weeks in the absence of diseas
  • Capecitabine
  • Fluorouracil
  • Leucovorin Calcium
  • Oxaliplatin
  • Veliparib

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 the
             following:

               -  Distance of the lowest tumor margin from the anal verge; and

               -  Intent for sphincter sparing surgical resection or not according to the primary
                  surgeon

          -  The tumor must be clinically determined to be locally advanced stage II or stage III
             rectal cancer, defined as meeting any ONE of the following criteria:

               -  Distal location: cT3-4 =< 5 cm from the anal verge, any N (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])

               -  Bulky: any cT4 with the majority of the untreated tumor < 12 cm from the anal
                  verge or below the peritoneal reflection as determined by the treating surgeon,
                  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)

               -  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 endoscopic ultrasound or abdominal/pelvic MRI (MRI is preferred);
                       CT scan with IV contrast is acceptable provided there is evidence of T4
                       and/or N2 disease; 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

          -  At least two (2) untreated core biopsy specimens from the untreated tumor
             (formalin-fixed, paraffin-embedded [FFPE]) must have been collected previously and be
             available for submission per protocol requirements

          -  Patients must have the ability to swallow and retain oral medication

          -  Absolute neutrophil count (ANC) must be >= 1200/mm^3

          -  Platelet count must be >= 100,000/mm^3

          -  Hemoglobin must be >= 10 g/dL

          -  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

          -  Alkaline phosphatase must be =< 3 x ULN for the lab

          -  Aspartate aminotransferase (AST) must be =< 3 x ULN for the lab;

               -  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

          -  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) and prothrombin time (PT)
             within 28 days before randomization must be WNL 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 done within 14 days before randomization must be negative (for women of
             childbearing potential only); pregnancy testing should be performed according to
             institutional standards

        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 CT
             scan with IV contrast (chest/abdomen/pelvis), with or without PET scan (preferred);
             MRI of the abdomen and pelvis and a chest x-ray (posterioranterior [PA] and lateral)
             is acceptable; (it is recommended that the same imaging tests that are performed
             before randomization be used at follow-up time points)

          -  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) >= 450ms

          -  Sensory or motor neuropathy >= grade 2

          -  Active inflammatory bowel disease (i.e., patients requiring current medical
             interventions or who are symptomatic) or have a history of abdominal surgery that may
             interfere with gastrointestinal motility or absorption

          -  Active seizure disorder uncontrolled by medication

          -  Any antineoplastic therapy for this cancer before randomization

          -  Synchronous colon cancer

          -  Other invasive malignancy within 5 years before randomization; exceptions are colonic
             polyps, non-melanoma skin cancer or carcinoma-in-situ of the cervix

          -  Chemotherapy 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)

          -  Major surgery within 4 weeks before randomization

          -  Any therapeutic pelvic radiation

          -  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 3 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 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:OS
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:DFS
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 disease progression during chemotherapy (prior to chemoradiation)
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 pathologic complete response
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 cCR
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 negative circumferential margin
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 completion of all cycles of neoadjuvant chemotherapy
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 completion of full course of chemoradiation
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 and sphincter function including quality of life
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:Incidence of toxicity including patient-reported toxicities using Common Terminology for Adverse Events version 4.0
Time Frame:30 days after last study treatment
Safety Issue:
Description:
Measure:Predictive markers
Time Frame:Up to 3 years
Safety Issue:
Description:Cox regression models will be used to evaluate markers for time-to-event variables. Logistic regression models will be used for binary variables. Models will control for stratification factors and possibly other prognostic variables (e.g. gender or treatment).
Measure:Radiographic findings
Time Frame:Up to 3 years
Safety Issue:
Description:Will explore the relationship between radiographic findings and pathologic outcomes.
Measure:Pathologic outcomes
Time Frame:Up to 3 years
Safety Issue:
Description:Will explore the relationship between radiographic findings and pathologic outcomes.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 8, 2018