D,L-MEthadone and mFOLFOX6 in Treatment of Advanced Colorectal Cancer

NCT05212012 | Active Not Recruiting Phase 1 DMC

• 2 other identifiers: AIO-KRK-01192024-519509-37-00
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 3

Brief Summary

This is a phase I/II-trial with D,L-methadone and mFOLFOX6 in the treatment of patients with histologically confirmed chemo-refractory colorectal carcinoma. The aim of the phase-I trial is to evaluate the toxicity-profile and the dose-limiting toxicity of D,L-methadone combined with mFOLFOX6. Furthermore, to estimate the maximum tolerated dose and the recommended dose for phase-II-trial in the treatment of patients with histologically confirmed colorectal carcinoma not amenable to or progressing while having received all standard therapies. The primary endpoint of the randomized phase-II study is to determine the disease control rate 12 weeks after randomization of patients with histologically confirmed advanced colorectal carcinoma upon treatment with D,L methadone plus mFOLFOX6 versus mFOLFOX6 alone. Overall response rate according to RECIST1.1, progression free survival (PFS), overall survival (OS), quality of life (QoL) according to the EORTC QLQc30 questionnaire, patient-reported outcomes and safety will be evaluated as secondary objectives.

Conditions

Chemo-refractory Colorectal Carcinoma

Keywords

chemo-refractory; colorectal carcinoma; D,L-methadone; mFOLFOX6

Outcome Measures

Primary Outcomes (2)

• Evaluation of the recommended dose for phase-II-trial

  Evaluation of the toxicity-profile of D,L-methadone and the dose-limiting toxicity (DLT) in combination with mFOLFOX6

  18 months

• Disease control rate 12 weeks after randomization (ITT-population)

  Evaluation of the disease control rate of D,L-methadone plus mFOLFOX6 compared to mFOLFOX6 alone in the treatment of patients with advanced colorectal cancer. The disease control rate is defined as response (CR or PR) or stabilization (SD) of the tumor disease at 12 weeks after randomization (DCR) according to RECIST1.1.

  12 weeks after randomization

Secondary Outcomes (7)

• Disease control rate (DCR) 12 weeks after randomization (per-protocol-population)

  12 weeks

• Overall response rate

  46 months

• patient diary

  46 months

• Progression-free survival

  after 46 months

• Overall survival

  46 months

Study Arms (1)

D,L-methadonehydrochloride + mFOLFOX6

EXPERIMENTAL

Dose Level D,L-methadone hydrochloride (Methasan® 10 mg/ml) In dose level I a maximum of 30 mg/day (15 mg (1,5 ml) 1-0-1) In dose level II a maximum of 35 mg/ day (17.5 mg (1,75 ml) 1-0-1) In dose level III a maximum of 40 mg/day (20 mg (2,0 ml) 1-0-1) Treatment with mFOLFOX6 every two weeks; will be administered: Oxaliplatin at a dose of 85 mg/m² iv over two hours (day 1) LV at a dose of 400 mg/m² iv over two hours (day 1) 5-FU at a dose of 2400 mg/m² iv over 46 hours (day 1-3)

Drug: Maximum tolerated dose, MTD: D,L-methadone hydrochloride (Methasan® 10 mg/ml)

Interventions

Maximum tolerated dose, MTD: D,L-methadone hydrochloride (Methasan® 10 mg/ml) DRUG

Dose Level D,L-methadone hydrochloride (Methasan® 10 mg/ml) In dose level I a maximum of 30 mg/day (15 mg (1,5 ml) 1-0-1) In dose level II a maximum of 35 mg/ day (17.5 mg (1,75 ml) 1-0-1) In dose level III a maximum of 40 mg/day (20 mg (2,0 ml) 1-0-1)

D,L-methadonehydrochloride + mFOLFOX6

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Advanced, histologically confirmed, metastatic colorectal carcinoma not suitable for resection and chemorefractory or 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)
• Microsatellite stable subset (MSS) of colorectal cancer
• 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.
• There must be an oxaliplatin free period of at least 6 months prior to start of the study medication.
• No polyneuropathy of \> grade 1
• Tumor-related ECOG performance status 0-2
• Anticipated life expectancy ≥ 12 weeks
• Creatinine clearance ≥ 30 ml/min
• Serum total bilirubin level ≤ 3 x ULN.
• ALT and AST ≤ 2.5 x ULN or ≤ 5.0 x ULN in the presence of liver metastasis (established after adequate biliary drainage)
• White blood cell count ≥ 3.5 x 106/ml, neutrophil granulocytes count ≥ 1,5 x 106/ml, platelet count ≥ 100 x 106/ml
• Pain that has to be controllable without concomitant use of opioids
• Signed informed consent according to ICH/GCP and national/local regulations (participation in translational research is obligate)
• 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
• Age ≥ 18 years

You may not qualify if:

• Microsatellite unstable CRC (MSIhigh)
• Chronic infectious diseases, immune deficiency syndromes
• Polyneuropathy \>grade I according to CTCAE V4.03
• Premalignant hematologic disorders, e.g. myelodysplastic syndrome
• Disability to understand and sign written informed consent document
• 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 follow-up
• Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrollment
• 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).
• Severe non-healing wounds, ulcers or bone fractions
• Evidence of bleeding diathesis or coagulopathy
• 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)
• 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.

Sponsors & Collaborators

• AIO-Studien-gGmbH: lead
• Deutsche Krebshilfe e.V., Bonn (Germany): collaborator

Study Sites (3)

Universitätsklinikum Hamburg Eppendorf - II. Med.

Hamburg, 20246, Germany

Location

Stauferklinikum Schwäbisch Gmünd

Mutlangen, 73557, Germany

Location

Universitätsklinikum Ulm - Innere Med. I

Ulm, 89081, Germany

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Maximum Tolerated Dose

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Toxicity Tests; Investigative Techniques; Toxicological Phenomena; Pharmacological and Toxicological Phenomena; Physiological Phenomena

Study Officials

• Thomas Seufferlein, Prof.Dr.med.

  Ulm University Hospital, Department of Internal Medicine I

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase I: 3+3 dose escalation study (non-randomized) - max. 18 participant after Phase I start with a Amendment Phase II: Open-label, 2:1 randomized, controlled trial - 64 participant Patients in the mFOLFOX6 alone arm are allowed to cross over and receive methadone hydrochloride in combination with mFOLFOX6 upon disease progress

Study Record Dates

• First Submitted: November 2, 2021
• First Posted: January 27, 2022
• Study Start: February 17, 2022
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: October 3, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

DE (3)