Clinical Trials /

Talimogene Laherparepvec, Chemotherapy, and Radiation Therapy Before Surgery in Treating Patients With Locally Advanced or Metastatic Rectal Cancer

NCT03300544

Description:

This phase I trial studies the best dose and side effects of talimogene laherparepvec in combination with 5-fluorouracil, leucovorin, oxaliplatin, capecitabine, and chemoradiation before surgery in treating patients with rectal cancer that has spread from where it started to nearby tissue and lymph nodes. Drugs used in immunotherapy, such as talimogene laherparepvec, may stimulate the body's immune system to fight tumor cells. Drugs used in chemotherapy, such as 5-fluorouracil, leucovorin, oxaliplatin, and capecitabine 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 talimogene laherparepvec, 5-fluorouracil, leucovorin, oxaliplatin, and capecitabine and chemoradiation before surgery may 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 1

Trial Eligibility

Document

Title

  • Brief Title: Talimogene Laherparepvec, Chemotherapy, and Radiation Therapy Before Surgery in Treating Patients With Locally Advanced or Metastatic Rectal Cancer
  • Official Title: A Phase I Study of Talimogene Laherparepvec (TALIMOGENE LAHERPAREPVEC) With Neoadjuvant Chemotherapy and Radiation in Adenocarcinoma of the Rectum

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01844
  • SECONDARY ID: NCI-2016-01844
  • SECONDARY ID: NCI10058
  • SECONDARY ID: 10058
  • SECONDARY ID: 10058
  • SECONDARY ID: UM1CA186688
  • NCT ID: NCT03300544

Conditions

  • Rectal Adenocarcinoma
  • Stage III Rectal Cancer AJCC v7
  • Stage IIIA Rectal Cancer AJCC v7
  • Stage IIIB Rectal Cancer AJCC v7
  • Stage IIIC Rectal Cancer AJCC v7
  • Stage IV Rectal Cancer AJCC v7
  • Stage IVA Rectal Cancer AJCC v7
  • Stage IVB Rectal Cancer AJCC v7

Interventions

DrugSynonymsArms
CapecitabineRo 09-1978/000, XelodaTreatment (T-VEC, capecitabine, chemoradiation)
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-2-9757Treatment (T-VEC, capecitabine, chemoradiation)
LeucovorinFolinic acidTreatment (T-VEC, capecitabine, chemoradiation)
Oxaliplatin1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669Treatment (T-VEC, capecitabine, chemoradiation)
Talimogene LaherparepvecICP34.5-, ICP47-deleted Herpes Simplex Virus 1 (HSV-1) Incorporating the Human GM-CSF Gene, Imlygic, JS1 34.5-hGMCSF 47- pA-, T-VECTreatment (T-VEC, capecitabine, chemoradiation)

Purpose

This phase I trial studies the best dose and side effects of talimogene laherparepvec in combination with 5-fluorouracil, leucovorin, oxaliplatin, capecitabine, and chemoradiation before surgery in treating patients with rectal cancer that has spread from where it started to nearby tissue and lymph nodes. Drugs used in immunotherapy, such as talimogene laherparepvec, may stimulate the body's immune system to fight tumor cells. Drugs used in chemotherapy, such as 5-fluorouracil, leucovorin, oxaliplatin, and capecitabine 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 talimogene laherparepvec, 5-fluorouracil, leucovorin, oxaliplatin, and capecitabine and chemoradiation before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of
      talimogene laherparepvec in combination with capecitabine and radiation in rectal cancer.

      SECONDARY OBJECTIVES:

      I. To establish safety and feasibility of the combination including complications from
      surgical resection II. To determine the neoadjuvant rectal (NAR) score of talimogene
      laherparepvec with chemotherapy and radiation.

      EXPLORATORY OBJECTIVES:

      I. To correlate genomic information including RAS, RAF mutation status with response, disease
      free survival (DFS) and/or overall survival (OS).

      II. To determine immunomodulatory changes following talimogene laherparepvec, chemotherapy
      and radiation treatment including proportions of immune cell infiltrates in serially
      collected peripheral blood and/or frozen tumor samples (pre-, on treatment, and at post
      progression).

      III. To identify magnetic resonance imaging (MRI)-based features including MRI
      circumferential margin (mrCRM) at baseline or post-therapy mrCRM, MRI tumor regression grade
      (mrTRG) to define determinants of response, DFS and OS.

      IV. To determine the disease free survival (DFS) and overall survival (OS) of talimogene
      laherparepvec with chemotherapy and radiation in patients undergoing curative resection.

      V. To determine the pathological complete response (pCR) rate of talimogene laherparepvec
      with chemotherapy and radiation.

      OUTLINE: This is a dose-escalation study of talimogene laherparepvec.

      Patients receive talimogene laherparepvec intralesionally via endoscopy on weeks 1, 4, 6, and
      8. Patients receive 5-fluorouracil intravenously (IV) by bolus and over 46 hours, leucovorin
      IV bolus, and oxaliplatin IV over 2 hours on weeks 2 and 4. Patients also receive
      capecitabine orally (PO) twice daily (BID) followed by radiation therapy for 28 fractions on
      days 1-5 of weeks 8-13. Patients undergo resection surgery on weeks 21-25.

      After completion of study treatment, patients are followed up for 30 days and up to 5 years
      thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (T-VEC, capecitabine, chemoradiation)ExperimentalPatients receive talimogene laherparepvec intralesionally via endoscopy on weeks 1, 4, 6, and 8. Patients receive 5-fluorouracil IV by bolus and over 46 hours, leucovorin IV bolus, and oxaliplatin IV over 2 hours on weeks 2 and 4. Patients also receive capecitabine orally PO BID followed by radiation therapy for 28 fractions on days 1-5 of weeks 8-13. Patients undergo resection surgery on weeks 21-25.
  • Capecitabine
  • Fluorouracil
  • Leucovorin
  • Oxaliplatin
  • Talimogene Laherparepvec

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed A) low lying (i.e. =< 6
             cm from the anal verge) rectal adenocarcinoma eligible for concurrent chemoradiation
             therapy to rectal tumor, B) if the treatment is palliative in the metastatic setting,
             no additional requirements for tumor size or nodal involvement is needed; C) if the
             treatment is in the neoadjuvant setting, the tumor must ALSO be high-risk locally
             advanced rectal cancer defined as T3-4, N+, and/or at risk for a positive radial
             margin (as determined by the surgeon)

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9 /L

          -  Hemoglobin >= 9 g/dL

          -  Platelets >= 100,000 x 10^9 /L

          -  Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients
             with Gilbert's syndrome, who can have total bilirubin < 3 mg/DL)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
             institutional ULN

          -  Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault
             formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min

          -  Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
             time (PTT) =< 1.5 x institutional unless the subject is on anticoagulant therapy (if
             the subject is receiving anticoagulant therapy, PT, and activated partial
             thromboplastin time [aPTT] must be within therapeutic range of intended use of
             anticoagulants)

          -  Patients must have signed informed consent indicating that they are aware of the
             investigational nature of the study, and are aware that participation is voluntary;
             patients must be made aware of their other treatment options

          -  Talimogene laherparepvec, as well as other therapeutic agents used in this trial
             including radiation and capecitabine, may cause fetal harm when administered to a
             pregnant woman; women of childbearing potential (WOCBP) is defined as any female who
             has experienced menarche and who has not undergone surgical sterilization
             (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is
             defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of
             other biological or physiological causes; WOCBP and men must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) prior to study
             entry, during the study participation, and for four months after the last dose of the
             drug; WOCBP must have a negative serum pregnancy test within 72 hours prior to
             enrollment and agree to use effective contraception throughout the treatment period
             and for 4 months after the last dose of study treatment; should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she should inform her treating physician immediately

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients who have had radiotherapy within < 4 weeks are ineligible

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > grade 1) except alopecia are ineligible

          -  Use of other investigational, chemotherapeutic or targeted drugs within 28 days (or
             five half-lives, whichever is shorter; with a minimum of 14 days from the last dose)
             preceding the first dose of talimogene laherparepvec and during the study are
             ineligible

          -  Patients who have previously been treated with talimogene laherparepvec, any other
             oncolytic virus or pelvic radiation are ineligible

          -  Patients with known active central nervous system (CNS) metastases are ineligible;
             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

          -  Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy
             to talimogene laherparepvec or any of its components, capecitabine, fluorouracil
             (5-FU) and / or oxaliplatin are ineligible

          -  Patients with a history or evidence of active autoimmune disease (e.g., pneumonitis,
             glomerulonephritis, vasculitis, or other); or history of active autoimmune disease
             that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive
             drugs or biological agents used for treatment of autoimmune diseases) within 2 months
             of enrollment are ineligible; (replacement therapy [e.g., thyroxine for
             hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy
             for adrenal or pituitary insufficiency] is not considered a form of systemic treatment
             for autoimmune disease)

          -  Patients with evidence of clinically significant immunosuppression such as the
             following are ineligible:

               -  Primary immunodeficiency state such as severe combined immunodeficiency disease

               -  Concurrent opportunistic infection

               -  Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid
                  doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment

          -  Patients with active herpetic skin lesions or prior complications of herpetic
             infection (e.g., herpetic keratitis or encephalitis) are ineligible

          -  Patients with viral infections requiring intermittent or chronic systemic (intravenous
             or oral) treatment with an antiherpetic drug (e.g., acyclovir), other than
             intermittent topical use are ineligible

          -  Patients with other viral infections are ineligible:

               -  Known to have acute or chronic active hepatitis B or hepatitis C infection

               -  Known to have human immunodeficiency virus (HIV) infection

               -  Prior therapy with viral-based tumor vaccine

               -  Received live vaccine within 28 days prior to enrollment

          -  Subject who is unwilling to minimize exposure with his/her blood or other body fluids
             to individuals who are at higher risks for herpes simplex virus (HSV)-1 induced
             complications such as immunosuppressed individuals, individuals known to have HIV
             infection, pregnant women, or children under the age of 1 year, during talimogene
             laherparepvec treatment and through 30 days after the last dose of talimogene
             laherparepvec are ineligible

          -  Patients with uncontrolled intercurrent illness including, but not limited to, active,
             non-colorectal malignancies requiring systemic therapy, ongoing or active infection,
             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
             psychiatric illness/social situations that would limit compliance with study
             requirements are ineligible

          -  Although no effects on embryo-fetal development have been observed in animal studies,
             adequate and well-controlled studies with talimogene laherparepvec have not been
             conducted in pregnant women; in addition, given the high risk of detrimental effects
             of other study agents including capecitabine, 5-FU, oxaliplatin and radiation on
             embryo-fetal development, the study treatment must be excluded in the following
             patients:

               -  Female subject is pregnant or breast-feeding, or planning to become pregnant
                  during study treatment and through 4 months after the last dose of talimogene
                  laherparepvec

               -  Female subject of childbearing potential who is unwilling to use acceptable
                  method(s) of effective contraception during study treatment and through 4 months
                  after the last dose of talimogene laherparepvec

               -  Sexually active subjects and their partners unwilling to use male or female latex
                  condom to avoid potential viral transmission during sexual contact while on
                  treatment and within 30 days after treatment with talimogene laherparepvec

          -  Patients that unable to swallow oral medications are ineligible

          -  Patients with a major surgical procedure, open biopsy, or significant traumatic injury
             within 28 days prior to initiation of therapy, or anticipation of need for major
             surgical procedure during the course of the study other than that defined by protocol
             are ineligible

          -  If patients require anticoagulation while on protocol, they should be switched from
             warfarin to another alternative anticoagulant such as low molecular weight heparin or
             oral direct factor Xa inhibitors as deemed appropriate by the treating physician for
             the duration they are on capecitabine (must be switched at least 1 week prior to
             starting capecitabine) to avoid drug-drug interaction of warfarin with capecitabine

          -  Patients with a known dihydropyrimidine dehydrogenase (DPD) deficiency are ineligible

          -  Patients who are unable to get MRIs due to any reason including pacemakers or
             automatic implantable cardioverter-defibrillator (AICD) are ineligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of talimogene laherparepvec (TVEC) in combination with capecitabine and radiation
Time Frame:4 weeks after surgery
Safety Issue:
Description:Assessed using the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 5.0.

Secondary Outcome Measures

Measure:Percent of planned dose intensity
Time Frame:Up to 5 years
Safety Issue:
Description:Descriptive statistics will be used to report results.
Measure:Pathological complete response
Time Frame:Up to 5 years
Safety Issue:
Description:Will be reported with proportions along with the appropriate confidence intervals.
Measure:Disease free survival
Time Frame:Up to 5 years
Safety Issue:
Description:Will be reported using Kaplan-Meier method.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:Will be reported using Kaplan-Meier method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

December 9, 2019