2.1 Primary objectiveTo assess the rate of no progression (NPR) at 8 weeks following treatment with the combination of gefitinib and fulvestrant in EGFR mutated patients who failed previous treatment with reversible EGFR TKI*s (gefitinib or…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint
After 8 weeks of treatment start all patients that are evaluated for tumour
response and are Stable Disease or better (according to RECIST criteria) will
be classified as *non-progressive*. The study drug will be of interest for
further study as single agent in this tumour type if at least 24/46 (52.2%) of
patients are *non-progressive* within 8 weeks. (Patients without post baseline
tumour assessment will be regarded as progressive in the interim and the final
analysis).
Secondary outcome
Secondary Efficacy Endpoints
Quantitative and qualitative toxicities of this regimen:
Toxicities in terms of quality and quantity will be measured according to CTC
AE 4.0
Duration of response for responding patients
Each subject will be assigned a best objective response. This is defined as the
best response recorded from the start of treatment until disease
progression/recurrence (according to RECIST criteria). To be assigned the
status of PR or CR, changes in tumour measurements must be confirmed by
repeated assessments that should be performed no less than 4 weeks after the
criteria for response are first met.
The Disease Control Rate is defined as the number of CR+PR+SD patients.
Objective response will be summarized in a descriptive manner.
The analysis of duration of tumour response will be based on responding
patients. Duration of response is defined as the time from first response to
the time of documented disease progression or death (assuming confirmation of
response at least 4 weeks after initial documentation). Subjects still
responding to treatment at the time of analysis will be treated as censored
observations for duration of response on the date of the last tumour
assessment.
Time to Progression or Death
The Time to Progression is defined as the time from start of treatment to the
date of the first documented progression (according to RECIST criteria) or the
date of death for any reason in the absence of PD.
Progression Free survival
PFS is defined as the time from date of randomization to date of first observed
disease progression (radiological or clinical, whichever is earlier) or death
due to any cause, if death occurs before progression is documented. The actual
date of tumour assessments will be used for this calculation. PFS for patients
without disease progression or death at the time of analysis will be censored
at the last date of tumour evaluation. PFS for patients who have no tumour
assessments after baseline will be censored at day 1.
Overall Survival
Overall survival will be determined from the date of start of treatment to the
date of death irrespective of the cause of death. Patients who have not died at
the time of the final analysis will be censored at the date of last contact.
Background summary
In the Western world lung cancer remains the first cause of cancer related
deaths in men and has surpassed that due to breast cancer in women (1).
Recently it has been recognized that a subgroup of patients with non-small cell
lung carcinoma (NSCLC) that harbour an activating Epidermal Growth Factor
Receptor (EGFR) mutation (exon 19 deletions and L858R point mutations) are
sensitive to treatment with EGFR Tyrosine Kinase Inhibitors (TKI*s). These
patients comprise approximately 10-15% of all patients with adenocarcinoma of
the lung. Recent phase III trials have shown that treatment with reversible
EGFR TKI*s (gefitinib, erlotinib) result in an unprecedented objective response
rate of approximately 70% and another 25% disease stabilization rate (2).
However, invariably these patients relapse and currently no effective treatment
is available. Correlative studies have shown that upon relapse several
resistance mechanisms are operational. Half the patients have a secondary EGFR
mutation known as the T790M mutation. It*s net result is that the affinity for
currently available EGFR TKI*s is decreased markedly so that these inhibitors
cannot effectively compete for ATP and signal transduction through the EGFR
signaling pathway is restored resulting in tumour growth. For these patients
treatment with irreversible EGFR TKI*s (afatinib) may be an option as was shown
in promising early clinical trials (3-5). Results from phase III studies are
soon expected (6). Approximately 10% of patients exhibit Met amplification in
their tumours upon relapse. Here, clinical research is focusing on simultaneous
inhibition of the EGFR and c-Met pathway. Resistance mechanisms in the
remaining 40% of patients to date are unclear. In the recent years it has
become apparent, at least from in vitro studies, that there is an interactive
cross-talk between the estrogen receptor pathway and the epidermal growth
factor receptor pathway in NSCLC cells (7) Substantial evidence has
accumulated that estrogen receptors are expressed in NSCLC. In particular, the
Estrogen Receptor B (ERb) has shown to be expressed in over 50% of resected
NSCLC of both men and women and is associated with adverse outcome (8-10). Lung
cancer cells respond to estrogens with proliferation and it is thought that
this effect is mainly mediated through the ERb pathway as it is this type of ER
that is expressed abundantly in both normal and malignant lung tissue (11).
Subsequent studies have shown that treatment of NSCLC cells in vitro with
oestradiol results in downregulation of EGFR, whereas treatment with the
antioestrogen fulvestrant increased EGFR expression (12). Modulation of the
EGFR pathway effects ERb expression: treatment with epidermal growth factor
reduced ERb expression whereas gefitinib, an EGFR TKI, increased it. These data
suggest that the two pathways can substitute for one another when either is
inhibited, whereas stimulation of one pathway shuts down the other. This
reciprocal effect provides the rationale for simultaneous targeting of both
pathways in lung cancer (7). Indeed, in vitro studies have shown that NSCLC
cells treated by fulvestrant and gefitinib in combination were more likely to
undergo apoptosis and the combination had significantly more antiproliferative
effects as compared to treatment with either agent alone (7). In addition,
there seems to exist a second type of ER-EGFR interaction in the nucleus that
is independent of estrogen. Although estrogen may be produced locally in the
lung, the former provides the rationale to test the combination of an
anti-estrogen and EGFR TKI in both men and women independent of menopausal
status (13).
Here, we propose to perform a phase II study of the combination of fulvestrant
and gefitinib in patients with relapsed EGFR mutated NSCLC. The combination of
fulvestrant 250 mg intramuscular every 28 days and gefitinib 250 mg per os
daily has been shown to be safe and well-tolerated in a pilot trial conducted
by ECOG including 22 relapsed unselected NSCLC patients (14). One patient
discontinued treatment due to toxicity (grade 2 keratitis) and one patient with
a history of heart failure and prior radiotherapy and pleural effusions
developed grade 4 dyspnea. The one-year survival rate was 23% and a median
survival of 33 weeks was obtained. Three patients had an objective tumour
response. Intensity of nuclear staining of ERb of at least 60% was found to
correlate with survival in 12 patients sampled. Recently the standard dose for
fulvestrant in metastatic breast cancer, where the product has it*s only
registration, changed from 250 mg monthly to 500 mg monthly plus a loading dose
of 500 mg at day 14 (ref: SPC Faslodex; www.ema.europa.eu). This higher dose
gives a better efficacy of the drug without adding additional toxicity (15).
Study objective
2.1 Primary objective
To assess the rate of no progression (NPR) at 8 weeks following treatment with
the combination of gefitinib and fulvestrant in EGFR mutated patients who
failed previous treatment with reversible EGFR TKI*s (gefitinib or erlotinib)
2.2 Secondary objective
- Quantitative and qualitative toxicities of this regimen
- Duration of response for responding patients
- Time to progression or death
- Progression free survival
- Overall survival
2.3 Additional exploratory study objectives
Correlation of RNA from trombocytes with time to progression and/or overall
survival
Study design
STUDY DESIGN
3.1 Study design
This will be a single-centre, open-label Phase II study.
3.2 Statistical design
Simon*s optimal two-stage design to test if the drug combination is effective.
3.3 Procedure for registration
After verifying that the patient meets all eligibility criteria, has signed the
Informed Consent Form, the investigator will request registration by sending in
the registration form to the VUMC hospital, Department of Pulmonary Diseases,
fax +3120-4444328. Patients will receive a registration number.
3.4 Study drugs
The doses and schedule of gefitinib will be 250 mg/day per os. For fulvestrant
the dose and schedule will be 500 mg injection intramuscular on day 1, 14, 28
and every 28 days thereafter. Fulvestrant will be provided free of charge as
part of the grant for this Investigator Sponsored Study by AstraZeneca.
3.5 Duration of treatment
Gefitinib and fulvestrant will be continued until unacceptable toxicity or
tumour progression. In case of documented tumour progression, patient will
discontinue the trial and will receive further treatment as per investigator
decision. In responding patients tumour assessments will be performed after 8
weeks of therapy. In case of documented tumour progression, patient will
discontinue the trial and will receive further treatment as per investigator
decision.
Recruitment is expected to be completed within 2 years of the registration of
the first patient. Patients will remain on treatment until disease progression,
withdrawal due to toxicity or withdrawal due to patients wish. The study will
be terminated after every patient had a follow up of at least 6 months. For
patients with complete remission (CR), partial response (PR) and stable disease
(SD), treatment will continue until progression and/or unacceptable toxicity
and/or patient withdrawal.
Intervention
Gefitinib: Patients will be treated with gefitinib 250 mg per os daily which
constitutes the standard registered dose for gefitinib.
Fulvestrant: Patients will receive an intramuscular injection of 500 mg monthly
plus a intramuscular loading dose of 500 mg at day 14 (that is: on day 1, day
14, day 28 and every 28 days thereafter).
Study burden and risks
Patients accrued to the study will have to visit the outpatient department at
baseline and every 4 weeks thereafter. An anamnesis, physical examination,
pregnancy test (if applicable), lab test, ECG, tumour biopsy and CT-scan will
be done at baseline. Anamnesis, physical examination and lab tests will be done
every 4 weeks when patients visit the outpatient department. Every 8 weeks a
CT-scan will be performed. On day 1, 14, 28 and monthly thereafter patients
will receive a fulvestrant injection.
Besides pregnancy test (if applicable) and fulvestrant administration, the
number of visits and procedures are not different from routine clinical
practice.
Postbus 7057
1007MB Amsterdam
NL
Postbus 7057
1007MB Amsterdam
NL
Listed location countries
Age
Inclusion criteria
1.Histologically or cytologically confirmed NSCLC locally advanced and metastatic disease stage IIIB and IV, that have an activating EGFR mutation, progressive on treatment with gefitinib or erlotinib. Patients with unknown mutation status that have exhibited a response to these agents or stable disease for at least 6 months while on treatment with gefitinib or erlotinib are also eligible
2. At least one unidimensionally measurable lesion meeting RECIST criteria
3. ECOG PS 0-2
4. Age > 18 years
5. Adequate organ function, including:
a. Adequate bone marrow reserve: ANC > 1.5 x 109/L, platelets > 100 x 109/L.
b. Hepatic: bilirubin <1.5 x ULN, AP, ALT, AST < 3.0 x ULN
AP, ALT, and AST <5 xULN is acceptable if the liver has tumour involvement
c. Renal: calculated creatinine clearance > 45 ml/min based on the Cockroft and Gault formula.
6. Signed informed consent
7. Male and female patients with reproductive potential must use an approved contraceptive method, if appropriate. Female patients with childbearing potential must have a negative serum pregnancy test within 14 days prior to study enrollment.
8. Estimated life expectancy >12 weeks
9. Patient compliance and geographical proximity that allow adequate follow up.
10. NSCLC with an activating sensitising EGFR TK mutation as determined by using a well-validated and robust methodology.
Exclusion criteria
1. Pregnant or lactating women
2. Patients who are poor medical risks because of non-malignant disease as well as those with active uncontrolled infection.
3. Documented brain metastases unless the patient has completed local therapy for central nervous system metastases and has been off corticosteroids for at least two weeks before enrollment.
4. Concomitant treatment with any other experimental drug under investigation.
5. Known severe hypersensitivity to gefitinib or any of the excipients of the product.
6. Presence of EGFR TK mutation reported to confer resistance to EGFR TKI: i.e., exon 20 point mutation (T790M or S768I EGFR) or exon 20 insertion as determined by using a well-validated and robust methodology.
7. Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease.
8. Concomitant use of known CYP 3A4 inducers such as phenytoin, carbamazepine, rifampicin, barbiturates, or St John's Wort.
9. Previous enrolment or treatment in the present study.
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-000345-12-NL |
| CCMO | NL39476.029.12 |
| OMON | NL-OMON28300 |