PERMAD: Personalized Marker-driven Early Switch to Aflibercept in Patients With Metastatic Colorectal Cancer

NCT02331927 | Unknown Phase 2 DMC

• 2 other identifiers: PERMAD2012-005657-24
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 3

Brief Summary

The primary objective of the two phase PERMAD trial is the evaluation of the impact of a personalized marker-driven treatment approach with early detection of progression and modification of treatment on cytokines and angiogenic factors (CAF) and efficacy. In regard of the two parts, the primary objective of the run-in phase (n=50 patients) with conventional switch of chemotherapy together with the anti-angiogenic agent is the determination of a distinct cytokines and angiogenic factor (CAF) profile during treatment with FOLFOX and bevacizumab, which allows early detection/prediction of progressive disease. The primary objective of the marker-driven randomized part (n=150 patients) with marker-driven switch of antiangiogenic agent and maintenance of chemotherapy is the evaluation of the efficacy of an early marker-driven switch of anti-angiogenic treatment (bevacizumab to aflibercept) This is a multicentre, multinational, open labeled, prospective, randomized, controlled phase II study designed to assess the clinical utility of an early marker driven change of anti-angiogenic treatment (bevacizumab to aflibercept) maintaining the chemotherapy backbone until definite radiological progression in first line treatment of patients with metastatic colorectal cancer. After completing the run in phase of the study, with at least 30 patients completing their first line treatment (due to progression, secondary resection or toxicity) and being evaluable for CAF analyses, the results will be reviewed by an Independent Data Monitoring Committee (IDMC). Based on that review the decision to continue with, modify or cancel the randomized part will be made. The primary endpoint of the run-in phase with conventional switch of chemotherapy together with the anti-angiogenic agent is:

• Progression free survival (PFS1) of first line treatment The primary endpoint of the randomized part with marker-driven switch of antiangiogenic agent and maintenance of chemotherapy is:
• Progression free survival rate at 6 months (PFSR@6) after first cycle after randomization.

Conditions

Metastatic Colorectal Cancer

Keywords

colorectal cancer; marker-driven; bevacizumab; aflibercept; cytokines; angiogenic factors; CAF

Outcome Measures

Primary Outcomes (2)

• Run-in phase: Progression free survival (PFS1) of first line treatment

  Run-in phase with conventional switch of chemotherapy together with the anti-angiogenic agent. Primary endpoint: • Progression free survival (PFS1) of first line treatment Randomized part with marker-driven switch of antiangiogenic agent and maintenance of chemotherapy. Primary endpoint: • PFS rate at 6 months (PFSR@6) after first cycle after randomization

  approx. 10-12 months

• Randomized part: PFS rate at 6 months after first cycle after randomization

  Randomized part with marker-driven switch of anti-angiogenic treatment

  6 months

Secondary Outcomes (9)

• Predictive value of CAF particularly PlGF and VEGF-B for early detection of progression during treatment with chemotherapy and bevacizumab

  approx. 10-12 months

• Determination and validation of a CAF profile based on PlGF and VEGF-B predicting tumor progression before radiologic progression

  approx. 10-12 months

• PFS1, after first cycle after randomization (PFSr) and of second line treatment (PFS2)

  approx. 20 months

• Time to randomization (TTR)

  approx. 10-12 months

• Overall survival (OS)

  5 years

Study Arms (2)

Randomized Part: Arm A

NO INTERVENTION

Conventional switch of chemotherapy together with the antiangiogenic treatment: Bevacizumab and mFOLFOX6 (continuation of same regimen until progressive disease (PD) according to RECIST v1.1, followed by switch to aflibercept and FOLFIRI after PD).

Ramdomized Part: Arm B

EXPERIMENTAL

Early marker-driven switch of anti-angiogenic agent and maintenance of chemotherapy: Bevacizumab and mFOLFOX6 will be administered until change of the CAF-profile and at least stable disease according to RECIST v1.1. Change to Aflibercept and mFOLFOX6 (change of bevacizumab to aflibercept and continuation of mFOLFOX6) until PD according to RECIST v1.1, followed by change to FOLFIRI after PD).

Biological: Aflibercept

Interventions

Aflibercept BIOLOGICAL

Early marker-driven switch of antiangiogenic treatment (bevacizumab to aflibercept) maintaining the chemotherapy backbone until definite radiological progression. compared to a conventional treatment approach of changing chemotherapy and antiangiogenic agent at time of radiologic progression.

Ramdomized Part: Arm B

Eligibility Criteria

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

You may qualify if:

• Patients with histologically confirmed diagnosis of colorectal cancer presenting with unresectable stage IV (UICC) disease (primary tumor may be present)
• Patients with at least one measurable lesion, with size \> 1 cm (RECIST v1.1)
• ECOG Performance status ≤ 2
• Life expectancy \> 3 months
• Age ≥18 years.
• Haematologic function: ANC ≥ 1.5 x 109/L, platelets ≥ 100 x109/L, hemoglobin ≥ 9 g/dl or 5.59 mmol/l
• Patients not receiving therapeutic anticoagulation must have an INR \< 1.5 and aPTT \< 1.5 x ULN within 7 days prior to enrollment. The use of full dose anticoagulants is allowed as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least two weeks at the time of enrollment.
• Adequate liver function as measured by serum transaminases (AST \& ALT) ≤ 2.5 x ULN (in case of liver metastases \< 5 x ULN) and total bilirubin ≤ 1.5 x ULN
• Adequate renal function: Serum creatinine ≤ 1.5 x ULN
• Signed, written informed consent
• At least 6 months after completion of adjuvant chemotherapy.

You may not qualify if:

• Treatment with any other investigational agent within 30 days prior to entering this study.
• Prior systemic or local treatment of metastatic disease.
• Prior adjuvant or neo-adjuvant chemotherapy/radiotherapy completed less than 6 months prior to study entry.
• Pre History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) (unless adequately treated with standard medical therapy) e.g. uncontrolled seizures.
• Fertile women (\< 1 year after last menstruation) and men of childbearing potential unwilling or unable to use effective means of contraception (adequate: intrauterine device, long-acting injection, hormon implant, vasectomy) during treatment and for 6 months after the end of treatment.
• Pregnancy or lactation
• Positive serum pregnancy test within 7 days of starting study treatment in premenopausal women and women \< 1 year after the onset of menopause.
• Past or current history (within the last 2 years prior to treatment start) of other malignancies except metastatic colorectal cancer (patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).
• Peripheral neuropathy NCI CTCAE-grade ≥ 1
• Known DPD-insufficiency.
• Active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as \> 4 loose stools per day)
• History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) haemoptoe or evidence of interstitial lung disease on baseline CT scan.
• Serious, non-healing wound, ulcer or bone fracture.
• Thrombosis or severe bleeding within 6 months prior to entry into the study (except for bleeding of the tumor before its surgical resection) and no evidence of bleeding diathesis or coagulopathy.
• Urine dipstick for proteinuria ≥ 2+. If urine dipstick is ≥ 2+, 24-hour urine must demonstrate ≤ 1 g of protein in 24 hours for patient to be eligible.

Sponsors & Collaborators

• University of Ulm: lead
• Hubertus-Wald-Cancer Center Hamburg, Germany: collaborator
• Sanofi: collaborator
• Assign Data Management and Biostatistics GmbH: collaborator

Study Sites (3)

University Medical Center Hamburg-Eppendorf

Hamburg, Germany

Location

Klinikum am Steinenberg Reutlingen

Reutlingen, 72764, Germany

Location

University of Ulm

Ulm, Germany

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

aflibercept

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

Study Officials

• Thomas Seufferlein, Prof. Dr.

  University of Ulm

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. Thomas Seufferlein

Study Record Dates

• First Submitted: September 10, 2014
• First Posted: January 6, 2015
• Study Start: March 1, 2015
• Primary Completion: March 1, 2020
• Study Completion: March 1, 2021
• Last Updated: September 20, 2019

Record last verified: 2019-09

Locations

DE (3)