Metastatic Colorectal CancerPhase 2PERMADNCT02331927
PERMAD: Personalized Marker-driven Early Switch to Aflibercept in Patients With Metastatic Colorectal Cancer
A Phase 2 study testing Aflibercept in people with Metastatic Colorectal Cancer, run by University of Ulm at 3 sites in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Colorectal Cancer
- What is being tested?
- Aflibercept
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 150 participants
- Where
- 3 sitesGermany
- Study dates
- Mar 2015to Mar 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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
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- 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.
- Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment.
- Clinically significant cardiovascular disease, for example CVA, myocardial infarction (≤ 12 months before treatment start), unstable angina, NYHA Class II CHF, arrhythmia requiring medication, or uncontrolled hypertension.
- Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications.
- Known hypersensitivity or contraindication to the drugs used in the trial (eg: aflibercept, 5-FU, folinic acid/ leucovorin, oxaliplatin, bevacizumab, irinotecan).
- Concomitant treatment with ASS > 325 mg/d or NSAIDs, known to inhibit platelet function, sorivudin or analog compounds or preparations of St. John's wort.
- Inability or unwillingness to comply with the protocol.
Trial locations and contacts
3 sites in 1 country.
Germany3 sites
University Medical Center Hamburg-Eppendorf
Hamburg
Klinikum am Steinenberg Reutlingen
Reutlingen, 72764
University of Ulm
Ulm
About this study
Official title: Personalized Marker-driven Early Switch to Aflibercept in Patients With Metastatic Colorectal Cancer (PERMAD-Trial) - a Multicenter, Multinational, Two Part, Phase II Trial
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)
Read more
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
- Being tested
- Aflibercept
- Keywords
- colorectal cancer, marker-driven, bevacizumab, aflibercept, cytokines, angiogenic factors, CAF
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AfliberceptBiological
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.
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: Biological: Aflibercept |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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
Measured: approx. 10-12 months
Determination and validation of a CAF profile based on PlGF and VEGF-B predicting tumor progression before radiologic progression
Measured: approx. 10-12 months
PFS1, after first cycle after randomization (PFSr) and of second line treatment (PFS2)
Measured: approx. 20 months
Time to randomization (TTR)
Measured: approx. 10-12 months
Overall survival (OS)
Measured: 5 years
Overall response rate (RR) and Secondary resection rate (sRR)
Measured: approx. 20 months
Toxicity, Quality of life (QoL)
Measured: approx. 20 months
Changes in CAF during early marker-driven switch and conventional treatment approach
Measured: approx. 20 months
Prognostic value of CAF at baseline and/or during treatment
Measured: approx. 20 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jan 2015 (estimated)
- Study startMar 2015
- Primary completionMar 2020 (estimated)
- Study completionMar 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metastatic Colorectal CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 150 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Ulm
- Sponsor type
- University, hospital or other
- Collaborators
- Hubertus-Wald-Cancer Center Hamburg, Germany, Sanofi, Assign Data Management and Biostatistics GmbH
- Responsible party
- Principal investigator, Thomas Seufferlein, University of Ulm
- Investigators
- Thomas Seufferlein, Prof. Dr., Principal investigator, University of Ulm
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02331927
- Sponsor's protocol ID
- PERMAD
- Other IDs
- 2012-005657-24
- Acronym
- PERMAD
- Status last verified
- Sep 2019
- First submitted
- 10 Sep 2014
- Last updated
- 20 Sep 2019
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Seufferlein T, Lausser L, Stein A, Arnold D, Prager G, Kasper-Virchow S, Niedermeier M, Muller L, Kubicka S, Konig A, Buchner-Steudel P, Wille K, Berger AW, Kestler AMR, Kraus JM, Werle SD, Perkhofer L, Ettrich TJ, Kestler HA. Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer-Results of the prospective multicenter PERMAD trial. PLoS One. 2024 Jun 14;19(6):e0304324. doi: 10.1371/journal.pone.0304324. eCollection 2024.
PubMed 38875244
Study at a glance
From the registry record, last updated by the sponsor on 20 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Personalized Marker-driven Early Switch to Aflibercept in Patients With Metastatic Colorectal Cancer (PERMAD-Trial) - a Multicenter, Multinational, Two Part, Phase II Trial
- ClinicalTrials.gov ID
- NCT02331927
- Acronym / sponsor ID
- PERMAD / PERMAD
- Conditions
- Metastatic Colorectal Cancer
- Keywords
- colorectal cancer, marker-driven, bevacizumab, aflibercept, cytokines, angiogenic factors, CAF
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 150 participants (actual)
- Lead sponsor
- University of UlmUniversity, hospital or other
- Collaborators
- Hubertus-Wald-Cancer Center Hamburg, Germany, Sanofi, Assign Data Management and Biostatistics GmbH
- Study start
- Mar 2015
- Primary completion
- Mar 2020 (estimated)
- Study completion
- Mar 2021 (estimated)
- First posted
- 6 Jan 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 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 | Biological: AfliberceptEarly 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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.
Key exclusion criteria (21 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AfliberceptEarly 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. | Biological | Ramdomized Part: Arm B |
Primary outcome
Run-in phase: Progression free survival (PFS1) of first line treatment
Time frame: approx. 10-12 months
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
Randomized part: PFS rate at 6 months after first cycle after randomization
Time frame: 6 months
Randomized part with marker-driven switch of anti-angiogenic treatment
9 secondary outcomes
Predictive value of CAF particularly PlGF and VEGF-B for early detection of progression during treatment with chemotherapy and bevacizumab
Time frame: approx. 10-12 months
Determination and validation of a CAF profile based on PlGF and VEGF-B predicting tumor progression before radiologic progression
Time frame: approx. 10-12 months
PFS1, after first cycle after randomization (PFSr) and of second line treatment (PFS2)
Time frame: approx. 20 months
Time to randomization (TTR)
Time frame: approx. 10-12 months
Overall survival (OS)
Time frame: 5 years
Overall response rate (RR) and Secondary resection rate (sRR)
Time frame: approx. 20 months
Toxicity, Quality of life (QoL)
Time frame: approx. 20 months
Changes in CAF during early marker-driven switch and conventional treatment approach
Time frame: approx. 20 months
Prognostic value of CAF at baseline and/or during treatment
Time frame: approx. 20 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Sep 2019.
- Derived from this study: PubMed 38875244Seufferlein T, Lausser L, Stein A, Arnold D, Prager G, Kasper-Virchow S, Niedermeier M, Muller L, Kubicka S, Konig A, Buchner-Steudel P, Wille K, Berger AW, Kestler AMR, Kraus JM, Werle SD, Perkhofer L, Ettrich TJ, Kestler HA. Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer-Results of the prospective multicenter PERMAD trial. PLoS One. 2024 Jun 14;19(6):e0304324. doi: 10.1371/journal.pone.0304324. eCollection 2024.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Seufferlein, Prof. Dr. principal investigator
University of Ulm
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Aflibercept in people with Metastatic Colorectal Cancer, run by University of Ulm at 3 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 20 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Run-in phase: Progression free survival (PFS1) of first line treatment (time frame: approx. 10-12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02331927, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Sep 2019.