Colorectal NeoplasmsPhase 1/2M14AFSNCT02450656
Afatinib and Selumetinib in Advanced KRAS Mutant and PIK3CA Wildtype Non-small Cell Lung Cancer
A Phase 1/2 study testing Afatinib, Selumetinib and Docetaxel in people with Colorectal Neoplasms and Gastrointestinal Neoplasms, run by The Netherlands Cancer Institute at 2 sites in Netherlands.
Trial summary
This is a multi-center open-label proof-of-concept study consisting of two parts: PART A - a phase I dose-finding study (3 + 3 classical design) evaluating the RP2D of afatinib in combination with selumetinib in KRASm NSCLC; and PART B - a randomized phase II study investigating the progression free survival and… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colorectal Neoplasms, Gastrointestinal Neoplasms, Pancreatic Neoplasms
- What is being tested?
- Afatinib, Selumetinib and Docetaxel
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 320 participants
- Where
- 2 sitesNetherlands
- Study dates
- Jun 2015to Dec 2019
- Phase
- Phase 1/2
- 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
- Histological or cytological proof of advanced NSCLC; for PART B: treated with first line therapy for metastatic disease only.
- Written documentation of a known pathogenic KRAS (exon 2, 3 or 4) mutation and PIK3CA wildtype (defined as absence of mutations in exon 9 and 20)
- Able and willing to give written informed consent
- Able and willing to undergo blood sampling for PK and PD analysis
- Life expectancy >=3 months allowing adequate follow up of toxicity evaluation and antitumor activity.
- WHO performance status of 0 or 1.
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- Able and willing to undergo a tumor biopsies prior to start, after two weeks (part A only) and upon progression of disease
- Measurable disease according to RECIST 1.1
- Adequate organ system function measured by laboratory values
Who cannot join
- Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment.
- History of another malignancy Exception PART A: Patients who have been disease-free for at least 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent second malignancies are eligible. Exception PART B: Adequately treated carcinoma in situ of the cervix and adequately treated basal cell carcinoma of the skin. 3. Symptomatic or untreated leptomeningeal disease.
- Symptomatic brain metastasis.
- Patients previously treated with any drug combination known to interfere with EGFR, HER2, HER3, HER4 or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK and ERK.
- History of interstitial lung disease or pneumonitis
- Radio-, immuno- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed.
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- Opthalmological diseases
- Patients with left ventricular ejection fraction (LVEF) < 55%
- Patients with cardiac comorbidities
- Concomitant or recent use (in the past 14 days) of strong inhibitors and inducers of CYP1A2, CYP2C19, CYP3A4, 3A5 and P-glycoprotein (P-gp)
Trial locations and contacts
2 sites in 1 country.
Netherlands2 sites, 2 recruiting
- Recruiting
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Amsterdam, 1066CX
F Opdam, MD, PhD
F Opdam, MD, PhD
- Recruiting
UMC St. Radboud Nijmegen
Nijmegen, Gelderland, 6525GA
Carla ML van Herpen, MD, PhD, +31243610353, Carla.vanHerpen@radboudumc.nl
Carla ML van Herpen, MD, PhD
About this study
Official title: Phase I/II Study With the Combination of Afatinib and Selumetinib in Advanced KRAS Mutant Positive and PIK3CA Wildtype Non-small Cell Lung Cancer
This is a multi-center open-label proof-of-concept study consisting of two parts: PART A - a phase I dose-finding study (3 + 3 classical design) evaluating the RP2D of afatinib in combination with selumetinib in KRASm NSCLC; and PART B - a randomized phase II study investigating the progression free survival and safety of selumetinib/afatinib combination therapy compared to standard of care chemotherapy in KRASm NSCLC.
- Conditions
- Colorectal Neoplasms, Gastrointestinal Neoplasms, Pancreatic Neoplasms, Carcinoma, Non-Small-Cell Lung
- Being tested
- Afatinib, Selumetinib, Docetaxel
- Medical subject headings
- Colorectal Neoplasms, Gastrointestinal Neoplasms, Pancreatic Neoplasms, Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AfatinibDrug
Also called BIBW2992
Tablet
SelumetinibDrug
Also called AZD6244
Capsule
DocetaxelDrug
| Study group | Role | What they receive |
|---|---|---|
| Afatinib plus selumetinib | Experimental | Combination of afatinib and selumetinib at the optimal dose and regimen as determined in the phase I part of this study Receives: Drug: Afatinib; Drug: Selumetinib |
| Control | Active comparator | Standard-of-care second line treatment for non small cell lung cancer (docetaxel) Receives: Drug: Docetaxel |
What is being measured
The primary outcome is the main question the study is designed to answer.
Dose Limiting Toxicities (Phase I)
Incidence of DLTs in the first treatment cycle
Measured: Cycle 1 (4 weeks)
Progression Free Survival (Phase II)
PFS measured by RECIST v 1.1
Measured: CT scan every 6 weeks and monthly phone call until start of subsequent anticancer therapy or until all patients have been followed up for at least 18 months of have been lost to follow up, whichever occurs first
Secondary outcomes (3)
Tolerability (Incidence and severity of adverse events per CTCAE v4.03)
Incidence and severity of adverse events per CTCAE v4.03
Measured: Up to 28 days after last study drug intake
Plasma concentrations of afatanib and selumetinib
Plasma concentrations of afatanib and selumetinib will be measured at day 1,2,4,8,15, 22 in cycle 1, on day 1 and 2 in cycle 2 and subsequently before every treatment cycle to determine pharmacokinetics of both substances in combination and interindividual differences after a single dose and after multiple doses.
Measured: On day 1, 2, 4, 8, 15, 22 in cycle 1, on day 1 and 2 in cycle 2 and subsequently at every treatment cycle pre-dose
Efficacy (Phase II) (Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1)
Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1
Measured: Assessed by CT scans every 6 weeks and by monthly phone call until all patients have been followed up for at least 18 months or have been lost to follow up, whichever occurs first.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 May 2015 (estimated)
- Study startJun 2015
- Primary completionMay 2019 (estimated)
- Study completionDec 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Colorectal NeoplasmsStudies of the same condition, open and under way.
- More trials run by The Netherlands Cancer InstituteThe sponsor's other registered studies.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 320 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Netherlands Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca, Boehringer Ingelheim
- Responsible party
- Sponsor
- Investigators
- F Opdam, MD, PhD, Principal investigator, The Netherlands Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02450656
- Sponsor's protocol ID
- M14AFS
- Acronym
- M14AFS
- Status last verified
- Aug 2018
- First submitted
- 13 Nov 2014
- Last updated
- 27 Aug 2018
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Study With the Combination of Afatinib and Selumetinib in Advanced KRAS Mutant Positive and PIK3CA Wildtype Non-small Cell Lung Cancer
- ClinicalTrials.gov ID
- NCT02450656
- Acronym / sponsor ID
- M14AFS / M14AFS
- Conditions
- Colorectal Neoplasms, Gastrointestinal Neoplasms, Pancreatic Neoplasms, Carcinoma, Non-Small-Cell Lung
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 320 participants (estimated)
- Lead sponsor
- The Netherlands Cancer InstituteUniversity, hospital or other
- Collaborators
- AstraZeneca, Boehringer Ingelheim
- Study start
- Jun 2015
- Primary completion
- May 2019 (estimated)
- Study completion
- Dec 2019 (estimated)
- First posted
- 21 May 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.
This is a multi-center open-label proof-of-concept study consisting of two parts: PART A - a phase I dose-finding study (3 + 3 classical design) evaluating the RP2D of afatinib in combination with selumetinib in KRASm NSCLC; and PART B - a randomized phase II study investigating the progression free survival and safety of selumetinib/afatinib combination therapy compared to standard of care chemotherapy in KRASm NSCLC.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Afatinib plus selumetinib | Experimental | Drug: Afatinib, Drug: SelumetinibCombination of afatinib and selumetinib at the optimal dose and regimen as determined in the phase I part of this study |
| Control | Active comparator | Drug: DocetaxelStandard-of-care second line treatment for non small cell lung cancer (docetaxel) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Histological or cytological proof of advanced NSCLC; for PART B: treated with first line therapy for metastatic disease only.
- Written documentation of a known pathogenic KRAS (exon 2, 3 or 4) mutation and PIK3CA wildtype (defined as absence of mutations in exon 9 and 20)
- Able and willing to give written informed consent
- Able and willing to undergo blood sampling for PK and PD analysis
- Life expectancy >=3 months allowing adequate follow up of toxicity evaluation and antitumor activity.
Key exclusion criteria (10 listed)
- Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment.
- History of another malignancy Exception PART A: Patients who have been disease-free for at least 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent second malignancies are eligible. Exception PART B: Adequately treated carcinoma in situ of the cervix and adequately treated basal cell carcinoma of the skin. 3. Symptomatic or untreated leptomeningeal disease.
- Symptomatic brain metastasis.
- Patients previously treated with any drug combination known to interfere with EGFR, HER2, HER3, HER4 or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK and ERK.
- History of interstitial lung disease or pneumonitis
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 |
|---|---|---|
| AfatinibAlso: BIBW2992Tablet | Drug | Afatinib plus selumetinib |
| SelumetinibAlso: AZD6244Capsule | Drug | Afatinib plus selumetinib |
| Docetaxel | Drug | Control |
Primary outcome
Dose Limiting Toxicities (Phase I)
Time frame: Cycle 1 (4 weeks)
Incidence of DLTs in the first treatment cycle
Progression Free Survival (Phase II)
Time frame: CT scan every 6 weeks and monthly phone call until start of subsequent anticancer therapy or until all patients have been followed up for at least 18 months of have been lost to follow up, whichever occurs first
PFS measured by RECIST v 1.1
3 secondary outcomes
Tolerability (Incidence and severity of adverse events per CTCAE v4.03)
Time frame: Up to 28 days after last study drug intake
Plasma concentrations of afatanib and selumetinib
Time frame: On day 1, 2, 4, 8, 15, 22 in cycle 1, on day 1 and 2 in cycle 2 and subsequently at every treatment cycle pre-dose
Efficacy (Phase II) (Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1)
Time frame: Assessed by CT scans every 6 weeks and by monthly phone call until all patients have been followed up for at least 18 months or have been lost to follow up, whichever occurs first.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Aug 2018.
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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.
F Opdam, MD, PhD principal investigator
The Netherlands Cancer Institute
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Afatinib, Selumetinib and Docetaxel in people with Colorectal Neoplasms and Gastrointestinal Neoplasms, run by The Netherlands Cancer Institute at 2 sites in Netherlands.
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 9 inclusion and 10 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 27 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Netherlands. 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Contact F Opdam, MD, PhD (+31 20 512 2446, f.opdam@nki.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Dose Limiting Toxicities (Phase I) (time frame: Cycle 1 (4 weeks)). 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?
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 27 Aug 2018.