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Intermittent or Continuous Panitumumab Plus FOLFIRI for RAS/B-RAF Wild-type Metastatic Colorectal Cancer (IMPROVE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04425239
Recruitment Status : Completed
First Posted : June 11, 2020
Last Update Posted : April 7, 2022
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute, Naples

Brief Summary:
The investigators hypothesize that intermittent first-line Panitumumab plus FOLFIRI is effective as the same regimen given continuously, in unresectable metastatic RAS and BRAF wild type colorectal cancer patients. Correlative studies on tumor and blood samples could identify potential biomarkers of efficacy and help defining personalized treatment strategy.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Stage IV Drug: Panitumumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 151 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Intermittent or Continuous Panitumumab Plus FOLFIRI for First-line Treatment of Patients With RAS/B-RAF Wild-type Metastatic Colorectal Cancer: a Randomized Phase 2 Trial
Actual Study Start Date : May 21, 2018
Actual Primary Completion Date : July 2, 2021
Actual Study Completion Date : April 3, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Panitumumab

Arm Intervention/treatment
Active Comparator: CONTINUOUS ARM:
Patients will receive Panitumumab plus FOLFIRI until progressive disease, unacceptable toxicity or informed consent withdrawal.
Drug: Panitumumab
Intermittent administation
Other Names:
  • Irinotecan
  • Fluorouracil plus folinic acid

Experimental: INTERMITTENT ARM:
Patients will have a treatment free interval until progressive disease (PD), when they will receive up to 8 cycles of Panitumumab plus FOLFIRI. In the presence of complete or partial response, or stable disease, non-progressing patients will undergo again to treatment free interval until PD, when they will restart treatment. Treatment cycling will continue till any PD on treatment.
Drug: Panitumumab
Continuous administation
Other Names:
  • Irinotecan
  • Fluorouracil plus folinic acid




Primary Outcome Measures :
  1. Progression-free Survival [ Time Frame: up to 1 year last patients randomized ]
    Progression Free Survival on treatment (PFSOT) is defined as the time from randomization to the first objective disease progression documented in patients undergoing treatment cycle (objective disease progression during treatment free intervals are excluded) or death due to any cause, whichever occurs first.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: up to 1 year last patients randomized ]
    Overall Survival is defined as the time from randomization to the date of death


Other Outcome Measures:
  1. Toxicities [ Time Frame: up to 1 year last patients randomized ]
    Toxicities will be assessed in terms of incidence of Adverse Events (AE) that will be graded according to the NCI CTC-AE Version 4.03 criteria

  2. Assessment of patients'-health-related quality of life [ Time Frame: up to 6 months last patients randomized ]
    Quality of Life will be assessed by the European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30, v.3.0 questionnaire at baseline and at week 12 and 24 during treatment, in both arms

  3. Overall Response Rate [ Time Frame: up to 1 year last patients randomized ]
    Objective Response Rate will be evaluated according to RECIST

  4. Duration of response [ Time Frame: up to 1 year last patients randomized ]
    calculated as the time from the date of the first documented response, complete (CR) or partial (PR), until the date of the first documented progression or death.

  5. Early Tumor Shrinkage [ Time Frame: up to 8 weeks last patients randomized ]
    Early Tumor Shrinkage is defined as the reduction of at least 20% in the sum of longest diameter of the target lesions at week 8 compared with baseline

  6. Depth of response [ Time Frame: up to 1 year last patients randomized ]
    Depth of response is defined as reduction in the sum of longest diameter of the target lesions at the nadir, compared with baseline,in the absence of new lesions or progression of non-target lesions

  7. Genetic Alterations on tumor samples [ Time Frame: up to 1 year last patients randomized ]
    To evaluate the prognostic and predictive value genetic alterations, by next generation sequencing performed on archived tumor samples or on newly obtained biopsies. Analysis is exploratory and will be performed retrospectively after the main study analysis is completed. Analysis will target mainly all relevant clinical mutation in KRAS, NRAS, BRAF, PI3K, EGFR, cKIT and PDGFR genes. Since the identification of new markers correlating with disease activity and the efficacy or safety of treatment are rapidly evolving, the definitive list of analyses remains to be determined; however, it will include a comparative baseline DNA mutational status analysis vs cfDNA

  8. Circulating tumor DNA (liquid biopsy) [ Time Frame: up to 1 year last patients randomized ]
    To evaluate potential biomarkers of primary and secondary resistance analyzing, by Next-generation sequencing, circulating tumor DNA obtained from blood samples ("liquid biopsy") collected at baseline, at week 8, 16 and thereafter every 8 weeks concomitantly with tumor assessment. Analysis of cfDNA mutations on peripheral blood is exploratory and will be performed retrospectively after the main study analysis is completed. Analysis will target mainly all relevant clinical mutation in KRAS, NRAS, BRAF, PI3K, EGFR, cKIT and PDGFR genes. Since the identification of new markers correlating with disease activity and the efficacy or safety of treatment are rapidly evolving, the definitive list of analyses remains to be determined; however, it will include a comparative baseline DNA mutational status analysis vs cfDNA

  9. Metabolomic profiling [ Time Frame: up to 1 year last patients randomized ]
    Metabolomic profiling in peripheral blood at baseline and during treatment evaluated by NMR Spectrometer (600 MHz). The metabolite assignments will be based on the comparison of chemical shifts and spin-spin couplings with reference spectra and tables present in the SBASE-1-1-1 database by AMIX package (Bruker, Biospin, Germany), the human metabolome database (HMDB) and the biological magnetic resonance database (BMRB).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent to study procedures and to molecular analyses;
  2. Histologically proven diagnosis of colorectal cancer with wildtype RAS and BRAF status in certified laboratories;
  3. Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease;
  4. At least one measurable lesion according to RECIST1.1 criteria;
  5. Availability of a tumor sample (primary and/or metastatic sites) for exploratory research;
  6. Age ≥ 18 years;
  7. ECOG PS ≤ 2;
  8. Life expectancy of at least 12 weeks;
  9. Previous adjuvant chemotherapy allowed only if more than 6 months elapsed between the end of adjuvant and first relapse;
  10. Neutrophils ≥ 1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥ 9 g/dl;
  11. Total bilirubin ≤1.5 time the upper-normal limits (UNL) of the normal values and ASAT (SGOT) and/or ALAT (SGPT) ≤ 2.5 x UNL (or < 5 x UNL in case of liver metastases) alkaline phosphatase ≤ 2.5 x UNL (or < 5 x UNL in case of liver metastases);
  12. Creatinine clearance ≥50 mL/min or serum creatinine ≤ 1.5 x UNL;
  13. Female with a childbearing potential and male subjects must be willing to use adequate contraception (barrier contraceptive measure, oral contraception, intrauterine device);
  14. Will and ability to comply with the protocol.

Exclusion Criteria:

  1. Previous treatment for metastatic disease;
  2. Radiotherapy to any site within 4 weeks before the study;
  3. Any contraindication to use Panitumumab, Irinotecan, 5-FU or folinic acid
  4. Known or clinically suspected brain metastases.
  5. History or evidence upon physical examination of CNS disease unless adequately treated.
  6. Ascites, pleural effusion or pericardial fluid requiring drainage in last 4 weeks.
  7. Diagnosis of interstitial pneumonitis or pulmonary fibrosis;
  8. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration or which, in the investigating physician's opinion, rules out the patient's participation in the study;
  9. Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), serious cardiac arrhythmia requiring medication;
  10. Treatment with any investigational drug within 30 days prior to enrolment;
  11. Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ;
  12. Lack of physical integrity of the gastrointestinal tract or history of acute or sub-acute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhea.
  13. Disease that is deemed potentially resectable.
  14. Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
  15. Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
  16. Breastfeeding
  17. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04425239


Locations
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Italy
Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale
Napoli, Italy, 80131
Sponsors and Collaborators
National Cancer Institute, Naples
Investigators
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Principal Investigator: Antonio Avallone, MD Istituto Nazionale dei Tumori di Napoli - IRCCS - Fondazione G. Pascale
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Responsible Party: National Cancer Institute, Naples
ClinicalTrials.gov Identifier: NCT04425239    
Other Study ID Numbers: IMPROVE
First Posted: June 11, 2020    Key Record Dates
Last Update Posted: April 7, 2022
Last Verified: September 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Cancer Institute, Naples:
metastatic colorectal cancer
RAS and BRAF wild type
intermittent therapy
liquid biopsy
panitumumab
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Folic Acid
Fluorouracil
Irinotecan
Panitumumab
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antidotes
Protective Agents
Vitamin B Complex