Randomized phase 3 study of intermittent or continuous Panitumumab plus FOLFIRI for first-line treatment of patients with unresectable left sided RAS/B-RAF wild-type metastatic colorectal cancer (IMPROVE-2 trial)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02], Diseases [C] - Digestive System Diseases [C06]

Trial duration

12 Jun 2024 → ongoing

Decision date (initial)

2024-04-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To investigate whether experimental intermittent treatment of Panitumumab plus FOLFIRI (given until progression during treatment or inacceptable toxicity) results effective in first line as the same regimen given continuously, in the treatment of metastatic left sided RAS/B-RAF wild-type colorectal cancer patients.
To assess whether an improvement in safety, tolerability and quality of life can be achieved in the intermittent arm as compared to the continuous arm.
To explore potential biomarkers of primary and secondary resistance as well as to monitor treatment efficacy and toxicity on both tissue, primary tumors and resected metastases when available, and blood samples.

Conditions and MedDRA coding

Unresectable left sided RAS/B-RAF wild-type metastatic colorectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Written informed consent to study procedures and to correlative studies
2. Histologically proven left sided mCRC
3. RAS/BRAF wild-type and pMMR and/or MSS status assessed at local centers according to a validated method defined by EMA
4. Disease judged unresectable by the local multidisciplinary team.
5. Patient candidate to receive Induction treatment with FOLFIRI plus panitumumab as per standard clinical practice
6. No prior treatments (chemotherapy, radiation or surgery) for mCRC. Surgery for primary CRC tumor before starting treatment is allowed
7. Either sex aged ≥ 18 years
8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 at study entry
9. Imaging-documented measurable disease, according to RECIST 1.1 criteria
10. Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory. Additional analysis of polymorphisms uridine diphosphate-glycosyltransferase 1 (UGT1A1) enzyme is recommended but not mandatory
11. Adequate bone marrow hematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109 /L AND platelet count ≥ 100 x 109 /L AND hemoglobin ≥ 9 g/dL.
12. Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 2 in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5 X ULN
13. Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula)
14. Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range

Exclusion criteria 13

1. Prior malignancy within five years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
2. Prior chemotherapy or any other medical treatment for mCRC (previous adjuvant chemotherapy is allowed if terminated > 6 months previously)
3. Major surgical intervention within 4 weeks prior to enrollment
4. Pregnancy and breast-feeding
5. Any brain metastases
6. Complete deficiency of activity of dihydropyrimidine dehydrogenase (DPYD) or known UGT1A1 homozygosity
7. Required dose reduction of 5-fluorouracil in the past for toxicity
8. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study
9. History of poor co-operation, non-compliance with medical treatment, unreliability or any condition that may impair the patient's understanding of the Informed consent form
10. Participation in any interventional drug or medical device study within 30 days prior to treatment start
11. 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
12. History of interstitial pneumonitis or pulmonary fibrosis
13. History of corneal perforation or ulceration keratitis

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to Treatment Failure (TTF) between the two arms: TTF is defined as the time from randomization to the objective disease progression by RECIST 1.1 criteria occurred during the treatment (objective disease progression during treatment free intervals are excluded) or death due to any cause, whichever occurs first, or a treatment delay > 28 days for toxicity

Secondary endpoints 12

1. Objective Tumor Response Rate (ORR) assessed according to RECIST criteria 1.1
2. Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response.
3. Depth of response (DpR) assessed as the percentage of tumor shrinkage observed at the lowest point (nadir) compared with baseline.
4. Progression-free survival (PFS) measured as the time from the date of randomization until the date of the first observation of disease progression or death due to any cause, whichever occurs first.
5. Progression-free survival on treatment (PFSot) measured as the time from the date of randomization to the date of disease progression occurred during treatment or death due to any cause, whichever occurs first.
6. Overall survival (OS) calculated as the time from the date of randomization until the date of death from any cause.
7. Safety evaluated as adverse events graded according NCI CTCAE v 5.0.
8. Tolerability evaluated as longitudinal toxicity over time and adverse event burden score.
9. Time toxicity measured as hospital-free days
10. Quality of life (QoL) investigated through the EORTC QLQ-C30 and CR29 questionnaires-
11. Patient Report Outcome (PRO)-CTCAE with items dedicated in particular to diarrhea and skin toxicity to evaluate the effect of the treatment on the health-related QoL
12. We will also explore the prognostic and predictive value of next generation sequencing (NGS), from blood samples (“liquid biopsy”) collected at baseline, at week 16 and thereafter every 8 weeks and serum metabolomic profiling in peripheral blood evaluated by NMR Spectrometer (600 MHz) concomitantly with tumor assessment, and at progression of disease. as well as the potential to monitor treatment activity of at baseline and during treatment.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Sponsor organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Address

Via Mariano Semmola 52

City

Naples

Postcode

80131

Country

Italy

Scientific contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Antonio Avallone

Public contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Antonio Avallone

Locations

1 EU/EEA country · 48 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications