Comparison of two strategies that use the same drugs but with inverted sequence for the treatment of patients with metastatic colorectal cancer who have failed in previous therapies.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione GONO G.I.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

3 Dec 2020 → ongoing

Decision date (initial)

2024-09-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-513296-41-00

EudraCT number

2019-002834-35

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective of this trial is to compare the efficacy in terms of OS of panitumumab followed after disease progression by regorafenib (arm A) versus the reverse sequence (arm B) in chemorefractory mCRC patients with previous benefit from
first-line anti-EGFR-based treatment and with RAS/BRAF wt ct-DNA at the time of study entry.

Secondary objectives 1

1. Secondary objectives of this study are to evaluate the two proposed treatments in terms of: Duration of Progression-free Survival during the first-line of study treatment (1st- PFS); Duration of Progression-free Survival during the second-line of study treatment (2nd- PFS); Duration of Time to failure strategy (TFS); Objective Response Rate (ORR) during panitumumab and regorafenib; Overall Toxicity Rate; G3/4 Toxicity Rate; Translational analyses.

Conditions and MedDRA coding

Colorectal cancer spread at distance, RAS BRAF wild type pretreatted

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 22

1. Age ≥ 18 years
2. Written informed consent to molecular analyses.
3. Histologically proven diagnosis of CRC
4. At least one measurable lesion according to RECIST1.1
5. ECOG PS ≤ 1.
6. mCRC previously treated for metastatic disease with, or not considered candidates for, fluoropyrimidine, oxaliplatin, irinotecan and anti-angiogenic monoclonal antibody (bevacizumab or aflibercept);
7. RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E mutation) wt status of primary CRC or related metastasis (local laboratory assessment).
8. Previous first-line anti-EGFR-containing therapy producing at least a partial response or a stable disease ≥ 6 months;
9. At least 4 months elapsed between the end of first-line anti-EGFR administration and screening;
10. At least one line of therapy between the end of first-line anti-EGFR administration and screening;
11. Availability of plasma sample for liquid biopsy within 28 days prior enrolment
12. RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E mutation) wt status of ct-DNA at screening (central laboratory assessment by means of IdyllaTM ctKRAS-NRAS-BRAF Mutation Test, Biocartis, Inc.).
13. Written informed consent to study procedures
14. Life expectancy of at least 12 weeks
15. Availability of archival tumour tissue (primary tumour and metastases or at least one of the two) for biomarker analysis;
16. Availability of biological samples for translational molecular analyses
17. Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥ 9 g/dl.
18. Total bilirubin ≤ 1.5 fold the upper-normal limits (UNL), ASAT (SGOT) and/or ALAT (SGPT) ≤ 2.5 x UNL (or <5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or <5 x UNL in case of liver metastases).
19. Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL.
20. Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient
21. Subjects and their partners must be willing to avoid pregnancy during the trial and until 8 weeks after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator (barrier contraceptive measure or oral contraception)
22. Will and ability to comply with the protocol.

Exclusion criteria 17

1. Previous treatment with regorafenib.
2. Radiotherapy to any site within 4 weeks before the study.
3. Untreated brain metastases or spinal cord compression or primary brain tumours
4. Evidence of bleeding diathesis or coagulopathy
5. Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.
6. 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, serious cardiac arrhythmia requiring medication.
7. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment
8. Any previous venous thromboembolism ≥ NCI CTCAE Grade 4.
9. History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment
10. 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
11. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication
12. Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
13. Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies
14. Diagnosis of interstitial pneumonitis or pulmonary fibrosis.
15. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating administration of panitumumab and regorafenib
16. Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer).
17. Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (ofchildbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 8 weeks after the last trial treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is Overall Survival. OS is defined as the time from randomization to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive

Secondary endpoints 6

1. Overall Toxicity Rate is defined as the percentage of patients, relative to the total of enrolled subjects, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 5.0), during panitumumab and regorafenib
2. G3/4 Toxicity Rate is defined as the percentage of patients, relative to the total of enrolled subjects, experiencing a specific adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 5.0), during panitumumab and regorafenib.
3. 1st-Progression free survival (1st-PFS) is defined as the time from randomization to the first documentation of objective disease progression or death due to any cause, whichever occurs first.
4. 2nd-Progression free survival (2nd-PFS) is defined as the time from the beginning of the second-line study treatment to the documentation of objective disease progression according to RECIST 1.1 criteria or death due to any cause, whichever occurs first.
5. Time to Failure of strategy (TFS) is defined as the time from randomization till the first of any of the following events: a) death; b) disease progression according to RECIST 1.1 criteria on any treatment given after 1st progression. For patients that will not receive any treatment within 3 months after 1st progression, TFS will be equal to PFS.
6. Objective Response Rate (ORR) is defined as the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria, during panitumumab and regorafenib. The determination of clinical response will be based on investigator reported measurements. Responses will be evaluated every 8 weeks

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione GONO G.I.

Sponsor organisation

Fondazione GONO G.I.

Address

Via Goffredo Mameli 3/1

City

Genoa

Postcode

16122

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Public contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Third parties 4

Locations

1 EU/EEA country · 50 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 7 files

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

Application history

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