Primary objectivesPhase I:To determine the recommended phase 2 dose (RP2D) of the dacomitinib-PD-0325901 combination in patients with KRASm NSCLC Phase II:To determine the progression free survival of the dacomitinib/PD-0325901 combination compared…
ID
Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence of dose-limiting toxicities (DLTs)
Progression free survival (PFS) per RECIST version 1.1
Secondary outcome
Incidence and severity of adverse events
Overall response rate, duration of response, time to response and overall
survival (phase II only)
Plasma concentrations of dacomitinib, PD-0325901 and relevant metabolites
Baseline molecular status of potential predictive markers of tumor response
(BRAF, HRAS, KRAS, NRAS, PTEN, PIK3CA, MAPK1, MAPK2, ARAF, c-MET, EGFR etc.)
Gene alteration (baseline, relapse) in tumor tissue
Background summary
In a pre-clinical study, treatment of KRAS mutant (KRASm) colorectal cancer
(CRC) cell lines with a dual inhibitor of the human epidermal growth factor
receptor 2 (ErbB2) and epidermal growth factor receptor (EGFR) kinases, in
combination with a MEK-inhibitor resulted in synthetic lethality. MEK
inhibition alone in these cells resulted in a strong feedback activation of
ErbB receptors, causing primary resistance via subsequent activation of the
phosphoinositide 3-kinase (PI3K) pathway. Concomitant treatment with a MEK
inhibitor and a dual EGFR/ErbB2 inhibitor completely suppressed this feedback
activation and resulted in cell death. Subsequently, the anti-tumor activity of
this combination was confirmed in cell lines derived from KRASm non-small cell
lung cancer (NSCLC) and pancreatic cancer. Because of the histology-independent
activity of this concept and the similarities at a molecular level, it is
plausible that this combination has the same effect on KRASm driven CRC, NSCLC
and pancreatic cancer in patients. Hence, there is a strong rationale for
combining dacomitinib, an EGFR/ErbB2/ErbB4 inhibitor, and PD-0325901, a MEK
inhibitor, in patients with KRASm NSCLC.
Study objective
Primary objectives
Phase I:
To determine the recommended phase 2 dose (RP2D) of the dacomitinib-PD-0325901
combination in patients with KRASm NSCLC
Phase II:
To determine the progression free survival of the dacomitinib/PD-0325901
combination compared to standard of care therapy in patients with KRASm NSCLC
Secondary objectives
- To characterize the safety and tolerability of dacomitinib in combination
with PD-0325901.
- To asses anti-tumor activity of dacomitinib in combination with PD-0325901.
- To determine the pharmacokinetic profile of dacomitinib and PD-0325901 in
this combination.
- To explore genetic determinants of response to the dacomitinib-PD-0325901
combination
- To evaluate pharmacodynamic biomarkers
- To explore the potential mechanism of resistance to dacomitinib in
combination with PD-0325901, as measured by gene alterations/expression
profiles (baseline, relapse) in tumor tissue upon progression
Study design
This is a phase I/II multi-center open-label proof of concept study, consisting
of a two parts. Part A of this study is a pharmacological dose-finding study,
designed to identify the recommended phase 2 dose (RP2D) of the combination
regimen of dacomitinib plus PD-0325901 in patients with advanced KRASm NSCLC.
Part B is randomized cross-over study to perform a randomized comparison of the
combination of dacomitinib and PD-0325901 versus standard of care therapy in
patients with advanced KRASm NSCLC
Intervention
In phase I, all patients will be treated with dacomitinib + PD-0325901. Start
doses are dacomitinib 30 mg once daily and PD-0325901 2 mg twice daily during
the first 21 days of every 28 day cycle. Guided by toxicity of this treatment,
the doses of both compounds can be escalated in new cohorts of patients to be
able to determine the recommended phase II dose.
In phase II, patiens will be randomized to be treated with the recommended
phase II dose of dacomitinib + PD-0325901 or with the standard of care second
line treatment for NSCLC (docetaxel,). Upon progression after dacomitinib +
PD-0325901, patients will cross-over to the comparator arm with standard of
care therapy and vice versa.
Study burden and risks
Possible risks with venapunctions is the development of a heamatoma at the
place of venapunction. Possible risks of tumor biopsies are mild pain during
anasthesia and the place where the biopsy is taken can become sensitive an
mildly painful during a few days. With biopsies from pulmonary tissue, there is
a slight risk of a pneumothorax.
Dacomitinib and PD-0325901 are non-registered drugs. Frequently occurring
adverse events with monotherapy of these compounds include: diarrhea, nausea,
fatigue and skin related adverse events.
Docetaxel is registered for the treatment of NSCLC. Frequently occurring
adverse events are: stomatitis, diarrhea, nausea, cmiting, alopecia, skin
related toxicities and hematological aberrations (anemia, leucopenia,
thrombocytopenia)
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Histological or cytological proof of metastatic NSCLC
2. Written documentation of a known pathogenic KRAS (exon 2, 3 or 4) mutation and PIK3CA wildtype (exon 9 and 20).
3. Age ><= 18 years.
4. Able and willing to give written informed consent.
5. WHO performance status of 0 or 1.
6. Able and willing to undergo blood sampling for PK and PD analysis.
7. Able and willing to undergo tumor biopsies prior to start, while on study treatment and upon progression of disease
8. All toxicities related to prior treatment should have resolved to CTCAE grade 1 or less (excluding alopecia)
9. Life expectancy ><= 3 months allowing adequate follow up of toxicity evaluation and antitumor activity.
10. Measurable disease according to RECIST 1.1 criteria
11. Adequate organ system function
Exclusion criteria
1. Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment.
2. History of additional prior malignancies.
3. Symptomatic or untreated leptomeningeal disease.
4. Symptomatic brain metastasis.
5. Patients previously treated with any targeted drug combination known to interfere with EGFR, HER-2, HER-3, HER-4 or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK and ERK.
6. History of interstitial lung disease or pneumonitis
7. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral dacomitinib/PD-0325901 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
8. Woman who are pregnant or breast feeding.
9. Unreliable contraceptive methods.
10. Radio-, immuno- or chemotherapy within the last 4 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed.
11. Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery.
12. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients.
13. Patients with a known history of hepatitis B or C.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-003299-10-NL |
| CCMO | NL45985.031.13 |