Clinical trial to compare the efficacy of two treatment sequencing schemes with chemotherapy (the regime called FOLFOX and FOLFIRI) in combination with biologic drugs (panitumumab and bevacizumab).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Asociacion Grupo Tratamiento De Tumores Digestivos

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Sep 2018 → ongoing

Decision date (initial)

2024-03-28

Transition trial

Yes

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-510967-41-00

EudraCT number

2018-000347-60

ClinicalTrials.gov

NCT03635021

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To compare the progression free survival rate (PFSR) at 36 months of FOLFOX + panitumumab followed by FOLFIRI + bevacizumab (Sequence 1) versus FOLFOX + bevacizumab followed by FOLFIRI + panitumumab (Sequence 2) in patients with wildtype RAS, primary left-sided, mCRC.

Secondary objectives 12

1. To compare the overall survival rate (OSR) at 36 months of Sequence 1 versus Sequence 2.
2. To compare the overall survival (OS) of Sequence 1 versus Sequence 2.
3. To compare total progression-free survival (PFS) from randomization to second progression or death (Total PFS=PFS in first-line + PFS in second-line) of Sequence 1 versus Sequence 2.
4. To determine PFS in first-line treatment and in second-line treatment in each Sequence arm.
5. To determine time to first-line treatment failure (progression, death or discontinuation due to toxicity) and to second-line treatment failure in each Sequence arm.
6. o evaluate the objective response rate (ORR) in first-line treatment and in second-line treatment in each Sequence arm.
7. To determine the proportion of patients with Early Tumour Shrinkage (ETS) in first-line treatment and in second-line treatment in each Sequence arm.
8. To evaluate Depth of Response (DpR) in first-line treatment and in second-line treatment in each Sequence arm.
9. To evaluate the disease control rate (DCR) and the duration of disease control (DDC) in first-line treatment and in second-line treatment in each Sequence arm.
10. To assess the duration of response in first-line treatment and in second-line treatment in each Sequence arm.
11. To assess the time to response in first-line treatment and in second-line treatment in each Sequence arm.
12. To assess the safety and tolerability of both Sequence arms as first-line treatment and as second line treatment.

Conditions and MedDRA coding

Metastatic colorectal cancer

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1) Man or woman of at least 18 years old.
2. 2) Capable to understand, sign and date an informed consent approved by an IEC.
3. 3) Histologically confirmed adenocarcinoma of the left colon or rectum (originated in the splenic flexure, descending colon, sigmoid colon, or rectum) in patients with unresectable or non-potentially resectable (not amenable to radical surgery of metastases at the study inclusion) metastatic (M1) disease.
4. 4) Patients who had wild-type RAS status confirmed as per standard of care according to international guidelines prior to first-line initiation. *RAS analysis should include at least KRAS exons 2, 3 and 4 (codons 12, 13, 59, 61, 117 and 146) and NRAS exons 2, 3 and 4 (codons 12, 13, 59, 61 and 117)
5. 5) At least one measurable lesion per RECIST criteria (version 1.1).
6. 6) ECOG performance status < 2.
7. 7) Adequate bone marrow function: neutrophils ≥1.5 x109/ L; platelets ≥100 x109/L; haemoglobin ≥9 g/dL.
8. 8) Hepatic, renal and metabolic function as follows: - Total bilirubin count ≤1.5 x upper limit of normal (ULN), serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) and serum glutamic oxaloacetic transaminase/aspartate aminotransferase (SGOT/AST) ≤ 2.5 x ULN (5 x ULN for subjects with liver involvement of their cancer) - Renal function, calculated as creatinine clearance or 24-hour creatinine clearance ≥ 50 mL/min.

Exclusion criteria 28

1. 1) History of prior or concurrent central nervous system metastases.
2. 2) History of another primary cancer, except: curatively treated in situ cervical cancer, or curatively resected non-melanoma skin cancer, or other primary solid tumour curatively treated with no known active disease present and no treatment administered for ≥ 5 years before randomization.
3. 3) Prior chemotherapy or other systemic anticancer therapy for treatment of metastatic colorectal carcinoma (including adjuvant QT for resected stage IV disease)
4. 4) Prior adjuvant chemotherapy for colorectal cancer (stage I, II or III) terminated less than 6 months before metastatic disease was diagnosed.
5. 5) Unresolved toxicities of a previous systemic treatment that, in the opinion of the Investigator, make the patient unfit for inclusion.
6. 6) Prior use (as monotherapy or adjuvant treatment) of anti-EGFR antibody therapy (e.g.cetuximab), anti-VEGF or small molecule tyrosine kinase inhibitors (e.g. regorafenib).
7. 7) Prior approved or experimental antitumoral treatment ≤ 30 days before inclusion.Hormonal sustitutive treatment is allowed.
8. 8) Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiating study treatment or history of ventricular arrhythmia.
9. 9) Uncontrolled hypertension.
10. 10) History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest computed tomography (CT).
11. 11) Treatment for systemic infection < 14 days before the start of study treatment.
12. 12) Active acute or subacute intestinal occlusion and/or active inflammatory bowel disease or another bowel disease that causes chronic diarrhoea (defined as grade ≥ 2 diarrhoea according to NCI-CTCAE version 4.03).
13. 13) Clinically significant peripheral sensory neuropathy.
14. 14) Evidence of previous acute hypersensitivity reaction, of any grade, to any component of the treatment.
15. 15) Known mutation in the UGT1A1 gene or known dihydropyrimidine deficiency syndrome.
16. 16) Recent (< 6 months before the start of study treatment) gastroduodenal ulcer active or uncontrolled.
17. 17) Recent (< 6 months before the start of study treatment) pulmonary embolism, deep vein thrombosis, or another significant venous event.
18. 18) Pre-existing bleeding diathesis and/or coagulopathy with exception of well-controlled anticoagulation therapy (< 6 months before the start of study treatment).
19. 19) Recent (< 28 days prior to inclusion in the study) major surgical procedure (excluding diagnostic biopsy, placement of a central venous catheter, colonic stents, or any minor surgery), open biopsy, or significant traumatic injury not yet recovered from prior major surgery.
20. 20) History of any disease that may increase the risks associated with study participation or may interfere with the interpretation of study results.
21. 21) Known positive test for human immunodeficiency virus infection, hepatitis C virus, and chronic active hepatitis B infection.
22. 22) Any disorder that compromises the patient’s ability to provide written informed consent and/or comply with study procedures.
23. 23) Any investigational agent <30 days prior to inclusion.
24. 24) Pregnant or breastfeeding women.
25. 25) Full dose radiotherapy <28 days prior to inclusion in the study. Short course radiotherapy for local control of primary tumor or other palliative indication is allowed.
26. 26) Male or female of childbearing age who do not agree with taking adequate contraceptive precautions, (i.e. use double barrier contraception (such as diaphragm plus condoms) or abstinence during the course of the study and for 6 months after the last administration of study drug for women and men.
27. 27) The patient is unwilling or unable to meet the requirements of the study.
28. 28) Psychological, geographical, familiar or sociological conditions that potentially prevent compliance with the study protocol and follow-up schedule.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 36-month PFSR defined as the number of patients, who at 36 months after randomization, have not had second† or first†† disease progression nor died (due to any cause), over the total number of evaluable patients. **To see the full text please refer to the protocol section 4.1.

Secondary endpoints 16

1. 36-month OSR defined as the number of patients who at 36 months after randomization have not died over the total number of evaluable patients.
2. OS defined as the time from randomization to the date of death (due to any cause), with patients alive or lost to follow-up at the analysis data cut-off date censored at their last contact date.
3. Total PFS defined as the time from randomization to second disease progression (i.e. progression during the second-line treatment)* or death (due to any cause). Patients who start a new antitumoral treatment different to specified in the protocol will be considered censored at date of last tumor assessment. Patients with surgery of tumor will be follow to PFS until documented progression disease or death for any cause. **To see the full text please refer to the protocol section 4.1.
4. PFS in first-line treatment defined as the time from randomization to disease progression or death (due to any cause) during first-line treatment. Patients who start a new antitumoral treatment different to specified in the protocol will be considered censored at date of last tumor assessment. **To see the full text please refer to the protocol section 4.1.
5. PFS in second-line treatment defined as the time from the date of second-line treatment initiation to disease progression or death (due to any cause) during second-line treatment. Patients who start a new antitumoral treatment different to what is specified in the protocol will be considered censored at the date of last tumor assessment. **To see the full text please refer to the protocol section 4.1.
6. Time to first-line treatment failure defined as the time form randomization to disease progression, death (due to any cause) or discontinuation due to toxicity during first-line treatment.
7. Time to second-line treatment failure defined as the time from the date of second-line treatment initiation to disease progression, death (due to any cause) or discontinuation due to toxicity during second-line treatment.
8. Proportion of patients with an objective response (complete or partial response) per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria in first-line treatment and in second-line treatment.
9. Proportion of patients with ETS in first-line treatment and in second-line treatment. ETS will be defined as a reduction in tumour size ≥30% (RECIST 1.1 criteria) at the first evaluation (i.e. week 12)
10. DpR measured as the maximum decrease in target measurement (RECIST 1.1 criteria) during the complete course of evaluation in first-line treatment and in second-line treatment.
11. Proportion of patients with disease control (complete, partial response or stable disease) in first-line treatment and in second-line treatment.
12. Duration of disease control defined as time from first confirmed disease control to disease progression per RECIST 1.1 criteria or death (due to any cause) in first-line treatment and in second-line treatment. For patients with disease control who have not progressed or died at last observation, duration of disease control will be censored at their last evaluable disease assessment date.
13. Duration of response defined as time from first confirmed objective response to disease progression per RECIST 1.1 criteria or death in first-line treatment and in second-line treatment. For patients with response who have not progressed or died at last observation, duration of response will be censored at their last evaluable disease assessment date.
14. Time to response in first-line treatment defined as the time from randomization to the date of first confirmed objective response per RECIST 1.1 criteria during first-line treatment.
15. Time to response in second-line treatment defined as the time from the date of second-line treatment initiation to the date of first confirmed objective response per RECIST 1.1 criteria during second-line treatment.
16. Safety assessment will consist of monitoring adverse events (AEs), including AEs of special interest, serious AEs (SAEs) and laboratory safety parameters. AEs will be graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCICTCAE) version 4.03.

Investigational products

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

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Asociacion Grupo Tratamiento De Tumores Digestivos

Sponsor organisation

Asociacion Grupo Tratamiento De Tumores Digestivos

Address

Calle Tellez 30 Planta 1 Oficina 4

City

Madrid

Postcode

28007

Country

Spain

Scientific contact point

Organisation

Asociacion Grupo Tratamiento De Tumores Digestivos

Contact name

Clinical Team

Public contact point

Organisation

Asociacion Grupo Tratamiento De Tumores Digestivos

Contact name

Clinical Team

Third parties 2

Locations

2 EU/EEA countries · 56 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 27 files

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

Application history

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