A phase I/II trial of D,L-MEthadone and mFOLFOX6 in treatment of advanced colorectal cancer (MEFOX)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AIO-Studien gGmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Feb 2025 → 28 Feb 2026

Decision date (initial)

2024-11-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Deutsche Krebshilfe

External identifiers

EU CT number

2024-519509-37-00

EudraCT number

2019-004158-26

ClinicalTrials.gov

NCT05212012

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Phase I:
• Evaluation of the toxicity-profile of D,L-methadone and the doselimiting toxicity (DLT) in combination with mFOLFOX6
• Estimation of the maximum tolerated dose (MTD) of D,L-methadone hydrochlorid in the combination with mFOLFOX6
• Evaluation of the recommended dose for phase-II-trial (RPTD) of D,Lmethadone hydrochlorid
Phase II:
• Effect of mFOLFOX6 + D,L-methadone compared to mFOLFOX6 alone on disease control rate (DCR) defined as response (CR or PR) or stabilization (SD) of the tumor disease 12 weeks after randomization in ITT-analysis. DCR will be evaluated according to RECIST1.1 in patients with histologically confirmed chemorefractory colorectal carcinoma.

Secondary objectives 10

1. • DCR 12 weeks after randomization (per protocol analysis)
2. • Effect on tumor response according to RECIST 1.1
3. • Effect on progression free survival (PFS)
4. • Effect on overall survival (OS)
5. • Health related quality of life (EORTC QLQ-C30)
6. • Patient-reported outcomes
7. • Correlation of DCR, PFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (µ opioid receptor expression on tumor cells, ctDNA, transcriptome, miRNAarrays)
8. • Evaluation of the safety- and tolerability profile
9. • Evaluation of the methadone levels under treatment
10. • Correlation of µ opioid receptor expression in tumor tissue and efficacy

Conditions and MedDRA coding

Patients with advanced, histologically confirmed, metastatic colorectal carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. 1. Advanced, histologically confirmed, metastatic colorectal carcinoma not suitable for resection and chemorefractory. Previously employed chemotherapy regimens and agents should comprise the following: Fluoropyrimidines, oxaliplatin, irinotecan, antiangiogenic agents (bevacizumab, aflibercept or ramucirumab), anti-EFGR-mAbs (in case of all-Ras-wildtype and left-sided primary tumor) and Trifluridin/Tipiracil (TAS102)
2. 2. Microsatellite stable subset (MSS) of colorectal cancer
3. 3. Prior antineoplastic therapy or radiochemotherapy is allowed up to two weeks prior to start of the study medication. However, for the phase II part of the trial, failure of this strategy must be confirmed. In case of prior radiotherapy/radiochemotherapy the target lesion used for tumor evaluation must not be in the radiation field
4. 4. There must be an oxaliplatin free period of at least 6 months prior to start of the study medication
5. 5. No polyneuropathy of > grade 1
6. 6. Tumor-related ECOG performance status 0-2
7. 7. Anticipated life expectancy  12 weeks
8. 8. Creatinine clearance  30 ml/min
9. 9. Serum total bilirubin level ≤ 3 x ULN
10. 10. ALT and AST  2.5 x ULN or  5.0 x ULN in the presence of liver metastasis (established after adequate biliary drainage)
11. 11. White blood cell count ≥ 3.5 x 106/ml, neutrophil granulocytes count ≥ 1,5 x 106/ml, platelet count ≥ 100 x 106/ml
12. 12. Pain that has to be controllable without concomitant use of opioids
13. 13. Signed informed consent according to ICH/GCP and national/local regulations (participation in translational research is obligate)
14. 14. None of the following concomitant medications: MAO-B-Inhibitors, strong inductors or inhibitors of CYP3A4, antiarrhythmic drugs of class I and III or other drugs that have potential for QT-prolongation
15. 15. Age ≥ 18 years
16. 16. At least one measurable target lesion according to RECIST 1.1. Preirradiated or locally treated lesions must not be used as target lesions

Exclusion criteria 22

1. 1. Microsatellite unstable CRC (MSIhigh)
2. 2. Chronic infectious diseases, immune deficiency syndromes
3. 3. Polyneuropathy >grade I according to CTCAE V4.03
4. 4. Premalignant hematologic disorders, e.g. myelodysplastic syndrome
5. 5. Disability to understand and sign written informed consent document
6. 6. Past or current history of malignancies except for the indication under this study and curatively treated: ▪ Basal and squamous cell carcinoma of the skin ▪ In-situ carcinoma of the cervix ▪ Other malignant disease without recurrence after at least 3 years of
7. 7. Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrollment
8. 8. History of or evidence upon physical examination of CNS disease unless adequately treated (e.g. primary brain tumor, seizure not controlled with standard medical therapy or history of stroke)
9. 9. Severe non-healing wounds, ulcers or bone fractions
10. 10. Evidence of bleeding diathesis or coagulopathy
11. 11. Patients not receiving therapeutic anticoagulation must have an INR ≤ 1.4 or PTT ≤ 40 sec within 28 days prior to randomization. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution)
12. 12. Major surgical procedures or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgical procedure during the course of the study
13. 13. Pregnancy or breastfeeding women
14. 14. Use of cannabinoids because of overlapping and /or potentiating of potential side effects
15. 15. Concomitant daily use of opioids in the last 3 months including methadone prior start of study medication
16. 16. Subjects with known allergies to the study drugs or to any of its excipients
17. 17. Treatment with another investigational drug or participation in another interventional trial (within the 14 days prior randomization or 5 plasma half-lifes of the used investigational drug, whatever is longer)
18. 18. Congenital QT-syndrome
19. 19. Alcohol abuse
20. 20. Bronchial asthma
21. 21. Liver cirrhosis > Child-Pugh classification A
22. 22. Any psychological, familial, sociological or geographical condition potentially compromising compliance with the study protocol and the follow-up schedule; those conditions should be discussed with the patient prior to registration in the trial

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I: Evaluation of the toxicity-profile of D,L-methadone and the dose-limiting toxicity (DLT) in combination with mFOLFOX6 Estimation of the maximum tolerated dose (MTD) of D,L-methadone hydrochlorid in the combination with mFOLFOX6 Evaluation of the recommended dose for phase-II-trial (RPTD) of D,Lmethadone hydrochlorid
2. Phase II: Effect of mFOLFOX6 + D,L-methadone compared to mFOLFOX6 alone on disease control rate (DCR) defined as response (CR or PR) or stabilization (SD) of the tumor disease 12 weeks after randomization in ITT-analysis. DCR will be evaluated according to RECIST1.1 in patients with histologically confirmed chemorefractory colorectal carcinoma

Secondary endpoints 1

1. Disease control rate 12 weeks after randomization (per-protocolpopulation), overall response rate according to RECIST 1.1, patientreported outcomes, PFS, overall survival, quality of life, safety, correlation of μ opioid receptor expression in tumor tissue and efficacy

Investigational products

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

Test 1

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AIO-Studien gGmbH

Sponsor organisation

AIO-Studien gGmbH

Address

Kuno-Fischer-Strasse 8, Charlottenburg Charlottenburg

City

Berlin

Postcode

14057

Country

Germany

Scientific contact point

Organisation

AIO-Studien gGmbH

Contact name

Prof. Dr. med. Thomas Seufferlein

Public contact point

Organisation

AIO-Studien gGmbH

Contact name

Katrin Krause

Locations

1 EU/EEA country · 8 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 8 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