The purpose of this prospective, multi-center, open-label, two-stage phase II study is to assessthe efficacy of BKM120, as measured by determining the PFS, in patients with pretreatedmetastatic NSCLC that exhibits PI3K pathway activation. BKM120…
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Brief title
Condition
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
Primary Objective
• To evaluate the efficacy of BKM120 based on disease Progression Free Survival
(PFS)
after initiating BKM treatment as measured by using RECIST criteria, in
patients with
activated PI3K pathway recurrent or metastatic NSCLC
Secondary outcome
Secondary Objectives
• Objective Response Rate (ORR) (Appendix 5, Novartis guidelines based on RECIST
Version 1.1) in patients with activated PI3K pathway advanced NSCLC
• To determine Time to and Duration of Response
• To determine Disease Control Rate
• To determine Overall Survival
• To characterize safety of BKM120
Exploratory Objectives
• To assess the predictive role of PIK3CA mt and PTEN alterations in patients
treated with
BKM120
• To assess the overall Quality of Life
• To obtain data on biomarkers associated with the anti-tumor activity of BKM120
• To assess changes in target and downstream pharmacodynamic markers of PI3K
inhibition
upon progression
• To assess the molecular profile of the genes and the proteins relevant to
PI3K signaling
• To characterize the pharmacokinetics (PK) of BKM120, and, if deemed
appropriate of any
potential metabolite/s in at least 20 consenting patients with recurrent or
metastatic
NSCLC
Background summary
Metastatic NSCLC carcinoma carries a poor prognosis when it recurs after
previous
treatments. Therapeutic options following disease progression usually consist
of single-agent
chemotherapy (i.e. docetaxel or pemetrexed) or EGFR TKIs (i.e. erlotinib or
gefitinib).
However, these treatments have shown limited efficacy (NCCN 2010).
Some of the NSCLC tumors can exhibit a *genetic dependency* to PI3K pathway
activation,
which could benefit from therapeutic interventions targeting this pathway.
BKM120 is an
oral, potent and specific pan-class I PI3K-inhibitor currently being tested in
clinical trials.
Although pre-clinical (in vitro and in vivo) models carrying the PI3K
activation are limited,
studies provide some evidence of sensitivity to single-agent BKM120.
Study objective
The purpose of this prospective, multi-center, open-label, two-stage phase II
study is to assess
the efficacy of BKM120, as measured by determining the PFS, in patients with
pretreated
metastatic NSCLC that exhibits PI3K pathway activation. BKM120 will be
investigated in
two groups of NSCLC patients according to the histology of the cancer: squamous
and nonsquamous.
*
*
Study design
This is a prospective multi-center, open-label, multi-stage, two arm, Phase II
study to
investigate the efficacy and safety of BKM120 in adult patients with recurrent
or metastatic
non-small cell lung cancer (NSCLC) and activated PI3K pathway. PI3K pathway
activation
(independent of the EGFR mutational status) in this trial is being defined as
one of the
following:
1. PIK3CA mutation
2. PTEN mutation
3. PTEN negative (<10% protein expression by IHC).
The arms will enroll simultaneously and patients will be classified upon
enrollment into one
of two groups based on histopathology and the number of prior antineoplastic
lines of
treatment.
• Group 1: Diagnosis of squamous NSCLC that progressed after one prior
platinumbased
chemotherapy line for recurrent or metastatic disease
• Group 2: Diagnosis of non-squamous NSCLC that progressed after one or two
prior
antineoplastic therapy lines for recurrent or metastatic disease
In order to be preliminarily eligible, patients must be pre-screened to confirm
PI3K pathway
activation as defined above. Prescreening is part of the trial. Testing to
confirm PI3K pathway activation may be performed
by a Novartis designated lab or locally by the site within the allowable limits
of Table 3-1. If
the PI3K pathway definition to confirm pre-screening eligibility is PTEN
Negative, this
assessment must be performed by a central Novartis designated lab. Results from
a local lab
will not be accepted as confirmation of PTEN Negative.
An analysis will be conducted to explore the relationship between the PI3K
activating factors
(PIK3CA mutant and PTEN alterations) and the clinical outcomes. Therefore a
predefined
minimal number of PIK3CA mutated pts (at least 35% of all the population) will
be required
to be enrolled in the study. Priority order for the alterations will be
considered as follows:
PIK3CA mutations > PTEN mutations > PTEN negative, in order to constitute
mutually
exclusive subsets of patients (i.e. patients with PIK3CA mutations regardless
of PTEN status
vs. patients without PIK3CA mutations, but with PTEN mutations vs. patients
with neither
PIK3CA nor PTEN mutations, but with PTEN loss).
Prescreening/Screening - Known PI3K pathway activation
Prior to beginning the screening process, the PI3K pathway activation
confirmation must be
sent to Novartis staff who will closely monitor the accrual rates of patients
with PIK3CA
mutations, PTEN mutations and PTEN negative to ensure the appropriate number of
PIK3CA
mutant patients are identified and enrolled. The general study ICF should be
signed before
the screening assessments are initiated. All necessary screening assessments
must be
completed within 21 days of signing the ICF. Eligibility should be determined
according to
the inclusion/exclusion criteria as detailed in Section 4. Both a blood sample
for testing
PIK3CA mutations in circulating DNA and a representative tumor sample (either
archival or
fresh) for confirmatory analysis of PI3K pathway activation status will be
collected and
analyzed by a Novartis designated lab. While it is preferential to receive both
the blood
sample and tumor during the screening period, it is not required and enrollment
may occur
prior to collection.
Prescreening/Screening - Unknown PI3K pathway activation
If the PI3K pathway activation status is unknown, the patient must sign a
pre-screening ICF
so that pathway activation status can be confirmed. The pre-screening ICF will
allow for both
blood and tumor to be collected and shipped to a Novartis designated lab for
analysis. Blood
will be collected to analyze PIK3CA mutational analysis in circulating DNA and
either
archival tumor tissue (block or slides) or a fresh biopsy will be tested for
PI3K pathway
activation defined as: PI3K3CA mutation, PTEN mutation or PTEN negative (<10%
protein
expression by IHC). As there is no time dependency between signing the
pre-screening ICF
and general study ICF, sites are encouraged to pre-screen patients with
recurrent or metastatic
NSCLC at any time to assess the PI3K activation status for inclusion in the
trial at a later date.
Alternatively, sites may perform PIK3CA or PTEN mutational testing on tumor
tissue locally,
if feasible. Local assessment confirming PTEN Negative will not be accepted as
confirmation
of PI3K pathway activation as this must be performed centrally. Results of this
testing must
be sent to Novartis staff prior to beginning the screening process. Following
that notification,
the general study ICF should be signed and all screening assessments initiated
within 21 days
of signature. Eligibility should be determined according to the
inclusion/exclusion criteria as
detailed in Section 4.
The study will be conducted in a two-stage format. The pre-screening
requirements described
above apply to all patients in both stages of the trial.
Stage I
A total of 60 evaluable patients will be enrolled in Stage I, with 30 allocated
to each group.
At least 15 patients with PIK3CA mutations must be enrolled in both group 1 and
group 2.
All Stage I patients will receive BKM120 orally at a dose of 100 mg/day. Dosing
will occur
in continuous 21 day cycles where the first dose of BKM120 defines Day 1 of the
treatment
cycle. Dosing will occur until disease progression or discontinuation of
treatment due to
intolerable toxicity, patient decision or death. Patients will be assessed for
efficacy by
radiological imaging every 6 weeks following the start of BKM120. Dose delays
of any kind
should not delay or change the scanning frequency or projected dates from Cycle
1, Day 1.
Analysis will be performed in each group after 30 patients have been enrolled
and observed
for at least 12 weeks or after death or RECIST progression has been reported
for each patient.
The enrollment into the trial in group 1 and/or 2 will be stopped due to
futility if a Progression
Free Survival (PFS) rate < 50% at 12 weeks is observed. The groups may accrue
independently and the futility analysis for each group may be performed
independently of one
another. If either or both groups have a PFS rate >= 50%, enrollment into Stage
II will begin
immediately.
Stage II
Stage II will open pending a negative futility analysis in one or both groups
in Stage I of the
trial. A maximum of 120 evaluable patients will be enrolled in Stage II with 60
patients
allocated to each group. Within each group at least 20 patients with PIK3CA
mutations must
be enrolled. All patients enrolled into Stage II will be randomized in a 2:1
ratio (40:20) to
receive either BKM120 or chemotherapy. Group 1 patients may receive Docetaxel
while
Group 2 patients may receive either Docetaxel or Pemetrexed according to
investigator
choice.
Patients randomized to BKM120 will receive a continuous oral dose of 100
mg/day. Dosing
will occur in continuous 21 day cycles where the first dose of BKM120 or
chemotherapy
defines Day 1 of the treatment cycle. As in Stage I, dosing will occur until
disease
progression or discontinuation due to intolerable toxicity, patient decision or
death for all
patients. Patients will be assessed for efficacy by radiological imaging every
6 weeks
following the start of BKM120 or Docetaxel/Pemetrexed. Dose delays of any kind
should not
delay or change the scanning frequency or projected dates from Cycle 1, Day 1.
Enrollment/study inclusion
In order to determine and confirm the eligibility of the patient an eligibility
checklist must be
completed and provided to the sponsor by the investigator or designee once all
screening
procedures are completed prior to enrollment into the treatment period of the
trial via IRT.
If the patient is successfully registered in the IRT, the system will confirm
the inclusion of the
patient in the treatment period of the trial and in Stage II, indicate which
treatment the patient
should receive (BKM120 or chemotherapy). The patient must start study treatment
within 6
days of enrollment.
Treatment phase and efficacy follow-up period
Following study inclusion and initiation of study treatment (C1D1), the patient
should visit
the site on study days 10 and 21 of every cycle for the duration of the
treatment period for
ongoing safety assessments and chemotherapy dosing pending Stage II
randomization. For
full details of assessments at individual visits refer to Section 6.
Response to treatment will be determined locally according to Response Criteria
in Solid
Tumors (RECIST) (Appendix X) every 6 weeks. Patients will continue on therapy
until
disease progression or discontinuation of treatment due to intolerable
toxicity, patient decision
or death, at which point an End of Treatment (EOT) visit will be performed and
the End of
Treatment eCRF page will be completed.
In case the patient discontinues treatment prior to documented progression of
disease for any
reason other than patient decision or death, the 6-weekly tumor evaluations
will continue until
progression of disease is determined as per RECIST or the patient begins a new
antineoplastic
therapy (Appendix X).
All patients will have a visit 30 days after permanently discontinuing study
treatment for
safety purposes.
Cross-over to BKM120
Cross-over to BKM12 will only be allowed based on specific outcomes outlined
below. For
those patients enrolled into stage II of the study and randomized to receive
chemotherapy,
they may cross-over to BKM120 therapy after a documented progression of disease
by
RECIST (evaluated by the Sponsor Clinical team) assuming one of the following
efficacy
criterion is met:
1. At the end of stage I, a median PFS > 4.5 months is observed
2. If the above criterion 1 is not fulfilled, during stage II (with 25 events
in each group
recorded), the observed hazard ratio is 0.67 or less (translating into an
increased PFS
in BKM arm of > 1.5 months compared to chemotherapy arm, assuming an
exponential survival distribution).
Patients must also meet the inclusion/exclusion criteria of the study at the
time of cross-over
to receive BKM120 treatment. All active patients on chemotherapy at the time
cross-over is
enabled (meaning one of the two above conditions are met) will be eligible as
will those
future patients yet to be randomized. The Novartis study team will notify all
sites and
investigators if and when cross-over will be allowed. Once crossed over,
patients may
continue to receive BKM120 until disease progression or discontinuation due to
intolerable
toxicity, patient decision or death for all patients. Patients will be assessed
for efficacy by
radiological imaging every 6 weeks following the start of BKM120. Dose delays
of any kind
should not delay or change the scanning frequency or projected dates from the
start of the first
BKM cycle.
Survival follow-up
After disease progression or after treatment discontinuation, all patients in
both Stage I and II
will continue to be followed for survival every two months. The final analysis
will be
conducted after at least 50 patients PFS events have been observed in each
Stage II group.
The Study Evaluation Completion eCRF page should be completed at the 30 day
safety follow
up visit. The patient should then be followed for survival by the investigator
every 2 months
by clinical visits or telephone calls until death occurs, the patient is lost
to follow-up, or
withdraws consent for follow-up for survival. Further patient treatment with
other therapies
will be at the discretion of the investigator and should be reported in the
eCRF (antineoplastic
therapy since discontinuation of study treatment).
All patients will continue to receive study treatment for as long as he or she
continues to
receive benefit in the opinion of the investigator. This data will subsequently
be collected for
overall survival analysis.
Intervention
All patients will receive either BKM120 or chemotherapy in this trial. All
patients in Stage I
will receive only BKM120. Patients in Stage II, Group 1 will be randomized to
receive
BKM120 or Docetaxel. Patients in Stage II, Group 2 will be randomized to
receive BKM120
or either Docetaxel or Pemetrexed based on investigator choice for
chemotherapy.
Study burden and risks
Potential benefit
Overall, approximately 50% of the tested NSCLC cell lines showed sensitivity to
BKM120
(15 out of 28 nonsquamous cell lines; 3 out of 7 squamous cell lines).
The largest clinical experience is based on an ongoing Phase I first-in-man
study of single -
agent oral BKM120 [BKM120X2101]. This study has been designed as a Bayesian
doseescalation
trial with a MTD dose-expansion arm enrolling patients with advanced solid
tumors. The dose-escalation part enrolled 66 patients, and preliminary data
have recently been
reported (Baselga, ASCO 2010). The single agent MTD for oral BKM120
administered once
daily was defined at 100 mg/d. Forty-five patients were evaluable for efficacy
(assessed both
with Computed Tomography (CT) scan and Fluorodeoxyglucose-Positron Emission
Tomography (FDG-PET) scan). Two RECIST partial responses were observed and
confirmed
by CT scan.
Novartis Confidential Page 4
EU CTA M4.2.3.4 Study No. CBKM120D2201
The first patient was a 61 year-old female with metastatic breast cancer with
an invasive
poorly differentiated ductal carcinoma assessed as triple negative (ER-, PgR-,
HER2-),
PI3KCA wild type, PTEN IHC positive. Since 2006 she received many previous
anticancer
agents. As progressive disease developed (bulky lymph node involvement and
local breast
relapse), she was enrolled (April 2009) in the Phase I study of BKM120 in the
100 mg/day
cohort. A metabolic response (61% decrease in SUV) was observed after 2 cycles,
followed
by a RECIST partial response (52% tumor shrinkage) after 4 cycles. This patient
continues to
receive treatment beyond 21 cycles.
The second patient was a 52 year-old female with moderately differentiated
ductal metastatic
breast cancer, assessed as ER positive, HER2 negative, PI3KCA mutated (E545K &
H1047Y), PTEN IHC positive. She had been previously treated with several
antineoplastic
agents. When she received BKM120 at 100 mg/day (Jan 2010), she had measurable
metastases in the brain (one lesion), lung (3 lesions) and liver (one lesion).
At the first
radiological assessment after receiving 2 cycles of BKM120 treatment, a 19%
reduction of the
sum of the lesions was recorded. The RECIST partial response was confirmed at
the next
radiological assessment with a 75% reduction after receiving 4 cycles BKM120
treatment.
The TTP for this patient was 24 weeks.
Twenty-six patients (58%) had stable disease as best response. In this study
[BKM120X2101], three Caucasian patients with metastatic NSCLC carcinoma were
enrolled.
A 72 year old patient had a metastatic adenocarcinoma without activation of the
PI3K
pathway (PIK3CA wt, PTEN wt and IHC 100%). The patient underwent radical
surgery in
1999 and 2006 (for a local relapse), received external beam radiation therapy
(EBRT) and
subsequent adjuvant chemotherapy (carboplatin/paclitaxel/gemcitabine for 6
cycles). Her
disease relapsed again in November 2008, and she received erlotinib as the
first-line treatment
for her metastatic disease, with a TTP of 11 weeks. A very rapid progression
occurred also on
the second-line treatment with pemetrexed (TTP 8 weeks). On October 20th 2009
the patient
started BKM120 at 80 mg/day and she had stable disease as best response until
the disease
progressed on December 30th 2009 (TTP 11 weeks).
A second patient was a 55 year old man with metastatic NSCLC (adenocarcinoma
histology)
and activation of the PI3K pathway (PIK3CA wt, PTEN mt (P213S) and IHC<50%). He
received surgery for the primary tumor followed by adjuvant chemotherapy
(cisplatin/vinorelbine/gemcitabine for 6 cycles) in 2002. When the disease
relapsed in 2006,
he received multiple lines of treatment: docetaxel for 4 cycles as first-line;
everolimus/erlotinib as second-line; B12536 plus pemetrexed as third-line and
gemcitabine as
fourth-line treatment. On March 30th 2010 the patient started receiving BKM120
at a 100
mg/day. However, after 1 week the treatment was discontinued for symptomatic
progression
of CNS metastases (CNS was not radiologically assessed before study entry).
The third lung cancer patient was 52 years old with a metastatic bronchial
adenoid cystic
tumor. This was a rare histology compared to the most common ones included in
the NSCLC
group. This tumor did not show activation of the PI3K pathway (PIK3CA wt, PTEN
wt and
IHC 100%). The patient relapsed after a surgery performed in 2001, and on July
23rd 2009 the
patient started BKM120 at 100 mg/day. This patient is still receiving
treatment. Shrinkage of
some lung lesions has been observed, but the RECIST-defined best response is
stable disease.
Thus, these findings generate the hypothesis that some of the NSCLC tumors can
exhibit a
*genetic dependency* to PI3K pathway activation, which could benefit from
therapeutic
interventions targeting this pathway.
Potential risk:
From current clinical experience, special attention needs to be paid to rash,
impaired glucose
metabolism, neuro-psychiatric disorders, liver function test alteration and
pneumonitis.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
Patient has a histologically confirmed diagnosis of NSCLC with activated PI3K pathway as defined by PIK3CA mutation and/or PTEN mutation and/or PTEN Negative (<10% protein expression by IHC). ;For confirmation of the PI3K pathway activation status, the patient must sign a molecular prescreening ICF. The molecular prescreening ICF will allow tumortissue to be collected and shipped to a Novartis designated laboratory for analysis. A representative archival or fresh tumor biopsy must be available for shipping to a Novartis designated lab for molecular profiling. Prescreening is a study related assessment.;Patient has experienced objective progressive disease after the prior systemic antineoplastic treatment(s) for advanced NSCLC is/are required as follows:
group 1: diagnosis of squamous NSCLC that progressed after one prior systemic platinum based chemotherapy-line for metastatic disease
group 2: diagnosis of non-squamous NSCLC that progressed after one to two prior systemic antineoplastic therapy lines for metastatic disease.;ECOG performance status < 2
Exclusion criteria
Patient has received previous treatment with PI3K inhibitors;Patient in stage 2 only:
a Squamous patients: previous treatment with docetaxel
b Nonsquamous patients: previous treatment with docetaxel and pemetrexed;Patient with squamous NSCLC has received more than one line of chemotherapy treatment for metastatic disease: patient with non-squamous NSCLC has received more than two lines of systemic antineoplastic treatment for metastatic disease ;Patient with uncontrolled or symptomatic CNS metastases;Patient has any of the following mood disorders as judged by the Investigator or a Psychiatrist, or meets the cut-off score of >12 in the PHQ-9 or a cut-off of >15 in the GAD-7 mood scale, respectively, or selects a positive response of "1, 2, 3"to question number 9 regarding potential for suicidal thoughts ideation in the PHQ-0 (independent of the total score of the PHQ-9);Patient has active or history of cardiac disease
Design
Recruitment
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 |
---|---|
Other | 01297491 |
EudraCT | EUCTR2010-024011-14-NL |
CCMO | NL36749.068.11 |