Clinical Trials /

Induction Therapy With Panitumumab + mFOLFOX-6 in Rectal Cancer and Quadruple Wild-type Mutation Before Surgery

NCT03000374

Description:

Patients with rectal adenocarcinoma of intermediate risk (defined by magnetic resonance imaging [MRI]), without mutations in KRAS, BRAF, NRAS and PI3KCA, who are candidates for preoperative treatment, will receive a preoperative Induction therapy with 12 weeks of panitumumab with mFOLFOX-6 to evaluate the efficacy in terms of pathologic complete response (pCR)

Related Conditions:
  • Rectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Induction Therapy With Panitumumab + mFOLFOX-6 in Rectal Cancer and Quadruple Wild-type Mutation Before Surgery
  • Official Title: Preoperative Induction Therapy With 12 Weeks of Panitumumab in Combination With mFOLFOX-6 in an Enriched Population (Quadruple Wild-Type) of Patients With mrT3 Rectal Cancer of the Middle Third With Clear Mesorectal Fascia

Clinical Trial IDs

  • ORG STUDY ID: GEMCAD-1601
  • SECONDARY ID: 2016-002333-29
  • NCT ID: NCT03000374

Conditions

  • Rectal Cancer

Interventions

DrugSynonymsArms
PanitumumabVectibix 20 mg/mlPanitumumab + mFOLFOX-6
5Fluorouracil5-FUPanitumumab + mFOLFOX-6
OxaliplatinAny marketedPanitumumab + mFOLFOX-6
LeucovorinAny marketedPanitumumab + mFOLFOX-6

Purpose

Patients with rectal adenocarcinoma of intermediate risk (defined by magnetic resonance imaging [MRI]), without mutations in KRAS, BRAF, NRAS and PI3KCA, who are candidates for preoperative treatment, will receive a preoperative Induction therapy with 12 weeks of panitumumab with mFOLFOX-6 to evaluate the efficacy in terms of pathologic complete response (pCR)

Detailed Description

      Phase II, nonrandomized single-arm trial of preoperative treatment with mFOLFOX-6 and
      panitumumab in an enriched population of patients with rectal adenocarcinoma of intermediate
      risk, screened by MRI, without mutations in KRAS, BRAF, NRAS and PI3K. All patients enrolled
      in the study will receive 12 weeks of the investigational product (mFOLFOX-6 with
      panitumumab) every 14 days for six cycles, unless unacceptable toxicity occurs or progression
      is detected. After this treatment, response will be evaluated by diffusion-weighted MRI and
      endoscopy. In the absence of disease progression, patients eligible for R0 resection will
      undergo total mesorectal excision (TME). After surgery, patients will receive mFOLFOX6 x 6
      cycles. In the case of intolerance to FOLFOX-panitumumab, disease progression or
      ineligibility for R0 resection, patients will receive chemoradiotherapy with capecitabine 825
      mg/m2 every 12 hours concomitantly with radiotherapy (RT) with a total dose of 50.4 Gy. At
      the end of this treatment, patients will undergo TME between 6-8 weeks after finishing the
      CRT. If a patient has received 4 or more neoadjuvant cycles of FOLFOX-panitumumab before
      unacceptable toxicity or progression, it will be considered that the neoadjuvant treatment
      has been completed and the patient will have no additional neoadjuvant treatment but surgery.
      If the patient has received <4 cycles of neoadjuvant treatment, neoadjuvant CRT will be
      administered.

      If a patient has an acceptable toxicity or disease progression or a R0 surgery is not
      possible to be performed and the patient received CRT, the patient will be followed up for 24
      months, from the enrollment of the last patient in the trial, or until progression occurs, in
      order to assess progression-free survival and all the data regarding surgery and CRT will be
      recorded in the eCRF. If a patient withdraws consent and refuses to continue participating in
      the study, follow-up evaluations must be discontinued.
    

Trial Arms

NameTypeDescriptionInterventions
Panitumumab + mFOLFOX-6Experimental- Modified FOLFOX-6 regimen: 5-Fluorouracil (5-FU), oxaliplatin and leucovorin will be administered intravenously once every 14 days, according to the mFOLFOX-6 regimen: Day 1: Oxaliplatin 85 mg/m² in IV infusion of 250-500 mL and leucovorin 200 mg/m² IV, both injected over two hours, followed by 5-FU 400 mg/m2 in IV bolus and a 46-hour infusion of 5-FU 2400 mg/m². - Panitumumab will be administered intravenously (IV) in a dose of 6 mg/kg on day 1 every 14 days. Panitumumab will be supplied to sites by the study sponsor in 5-mL and 20-mL vials, at a concentration of 20 mg/mL. Treatment will continue until 6 cycles have been administered, followed by surgery, 5 weeks +/- 1 week after the last dose of neoadjuvant treatment
  • Panitumumab
  • 5Fluorouracil
  • Oxaliplatin
  • Leucovorin

Eligibility Criteria

        Inclusion Criteria:

          1. Signed and dated informed consent form, and willingness and ability to comply with the
             requirements of the protocol;

          2. Men or women with rectal cancer, age ≥ 18 and <75 years;

          3. Histologically documented adenocarcinoma of the rectum. All other histologic types are
             excluded. A biopsy of the rectal primary tumor must be available (between 1-4), with
             tumor representation > 50% in each sample. The samples will be sent to Val d'Hebron
             Institute of Oncology (VHIO) for molecular determination. The blocks of the biopsies
             will be sent included in paraffin.

          4. Rectal cancer candidate for R0 resection with preservation of the rectal sphincter.

          5. Tumors with the following characteristics on high-resolution thin-slice (3 mm) MRI:

               1. mrT3

               2. Tumors of the middle third, defined as tumors whose distal edge is ≤ 12 cm of the
                  anal verge or below the peritoneal reflection and above ≥ 2 cm of the anorectal
                  junction.

               3. Absence of MRF invasion, defined as a distance ≥ 1 mm between the tumor and the
                  fascia;

          6. Absence of mutations in KRAS (mutations in KRAS exon 2 [codons 12/13], exon 3 [codons
             59/61] and exon 4 [codon 117/146], NRAS (NRAS exon 2 [codons 12/13], exon 3 [codons
             59/61] and exon 4 [codons 117/146]), BRAF (exon 15 [codon 600] and PI3KCA in exons 9
             and 20

          7. ECOG performance status ≤ 2;

          8. Hematological status:

               -  Neutrophils (ANC) ≥ 1.5 x 109/L;

               -  Platelets ≥ 100 x 109/L;

               -  Hemoglobin ≥ 9 g/dL;

          9. Adequate renal function: serum creatinine <1.5 x upper limit of normal (ULN);

         10. Adequate liver function:

               -  Serum bilirubin ≤ 1.5 x ULN,

               -  Alkaline phosphatase < 5 x ULN,

               -  AST/ALT < 3 x ULN;

         11. Regular monitoring feasible;

         12. In women of childbearing potential, a negative serum pregnancy test within 1 week (7
             days) before the start of study treatment;

         13. Women must commit to using reliable and appropriate methods of contraception for up to
             at least six months after the end of the study treatment (when applicable). Men with a
             partner of childbearing potential must agree to use a method of contraception and
             their partners must use another contraceptive method for the duration of the trial.
             Sexual abstinence will be accepted as a contraception method, with the duration and
             considerations stablished by the investigator

        Exclusion Criteria:

          1. Mucinous adenocarcinoma.

          2. N2 lymph node involvement, defined as: 4 or more lymph nodes in the mesorectum showing
             morphological signs of metastatic involvement on MRI. A lymph node is considered
             malignant when:

               1. Short axis > 9 mm.

               2. Short axis 5-9 mm and ≥2 of the following criteria:

                  i Rounded appearance. ii Heterogeneous margin. iii Heterogeneous signal
                  intensity.

               3. Short axis < 5 mm AND round shape AND heterogeneous margin AND heterogeneous
                  signal intensity.

          3. Extramesorectal lymph node involvement: an involved extramesorectal lymph node is
             defined as a lymph node in the obturator area with a short axis > 8 mm, round shape
             and heterogeneous signal..

          4. Prior treatment with panitumumab or cetuximab;

          5. Preexisting permanent neuropathy (grade ≥ 2 NCI-CTCAE);

          6. Concomitant antitumor treatment not foreseen in the protocol (e.g., chemotherapy,
             targeted molecular therapy, immunotherapy);

          7. Treatment with any other investigational medicinal product within the 28 days prior to
             study entry;

          8. Other simultaneous or prior malignancy, except: i) properly treated uterine cervix
             carcinoma in situ, ii) basal or squamous cell skin carcinoma, iii) cancer in complete
             remission for a period > 5 years;

          9. Evidence of metastatic disease in additional studies or in the physical examination;

         10. Any other severe and uncontrolled nonmalignant disease, major surgery or traumatic
             injury in the last 28 days;

         11. Pregnant or breastfeeding women;

         12. Patients with known allergy to any excipient of the investigational products;

         13. Clinically significant cardiovascular disease, including myocardial infarction,
             unstable angina, symptomatic congestive heart failure or cardiac arrhythmia in the
             year before randomization in the study.

         14. Intestinal occlusion: In the case of intestinal occlusion, patients may be enrolled in
             the study after performing a derivative stoma.

         15. Interstitial Lung Disease
      
Maximum Eligible Age:74 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic complete response (pCR)
Time Frame:Up to 16-18 weeks after first treatment administration
Safety Issue:
Description:Pathologic CR is defined as the absence of viable tumor cells in the primary tumor and lymph nodes (ypT0N0).

Secondary Outcome Measures

Measure:Rates of R0 resection and free mesorectal fascia (or circumferential margin)
Time Frame:Up to 16-18 weeks after first treatment administration
Safety Issue:
Description:
Measure:Tumor regression grade (TRG)
Time Frame:Up to 16-18 weeks after first treatment administration
Safety Issue:
Description:the residual tumor after preoperative treatment is evaluated semi-quantitatively using the 5-point regression grading scale established by Dworak
Measure:Rate of tumor downstaging (mrT versus ypT)
Time Frame:Up to 16-18 weeks after first treatment administration
Safety Issue:
Description:
Measure:Quality of surgery
Time Frame:Up to 16-18 weeks after first treatment administration
Safety Issue:
Description:According to the histopathology report
Measure:Adverse events and changes in laboratory results
Time Frame:All AEs that occur up until 30 days after the last dose of investigational product will be recorded. Serious and nonserious AEs related with the study treatment that appear up until 30 days after the administration of the last dose should be reported.
Safety Issue:
Description:The adverse events will be encoded using the Medical Dictionary for Regulatory Activities (MedDRA), version 18.1 or later, and evaluated using the U.S. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0.
Measure:Surgical complications
Time Frame:Over 30 days after surgery.
Safety Issue:
Description:
Measure:Rate of local recurrence
Time Frame:At 3 years after recruitment
Safety Issue:
Description:
Measure:Distant metastasis rate
Time Frame:At 3 years after recruitment
Safety Issue:
Description:
Measure:Disease free survival
Time Frame:At 3 years after recruitment
Safety Issue:
Description:
Measure:Overall survival
Time Frame:At 3 years after recruitment
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Grupo Espanol Multidisciplinario del Cancer Digestivo

Last Updated

May 30, 2019