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Addition of the Gamma-Secretase Inhibitor RO4929097 (IND 109291) to Erlotinib in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

18 Years
Open (Enrolling)
Recurrent Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

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Trial Information

Addition of the Gamma-Secretase Inhibitor RO4929097 (IND 109291) to Erlotinib in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)


I. To define the maximum-tolerated dose (MTD) and toxicity of RO4929097 (gamma-secretase
inhibitor RO4929097) combined with erlotinib (erlotinib hydrochloride) in patients with
advanced non-small cell lung cancer (NSCLC). (Dose escalation portion) II. To assess whether
the probability of detectable tumor shrinkage or response by Response Evaluation Criteria in
Solid Tumors (RECIST) criteria correlates with pre-therapy immunohistochemistry (IHC) and
reverse phase protein array (RPPA) expression of Notch 1, 2, 3, and 4. (Dose escalation
portion) III. A preliminary, exploratory assessment will be performed with respect to
percent tumor shrinkage and the probability of response over the first 2 cycles of therapy.
(Expansion cohort) IV. A preliminary, exploratory assessment will be performed with respect
to change in tumor immunohistochemistry (IHC) scores and reverse phase protein array (RPPA)
expression for Notch 1, 2, 3, and 4 over the first 2 cycles of erlotinib. (Expansion cohort)


I. To perform a preliminary exploratory assessment of whether probability of detectable
tumor shrinkage/response correlates with pre RO4929097 presence in tumor of an activating
epidermal growth factor receptor (EGFR) mutation, the T790M EGFR mutation, met
proto-oncogene (c-MET) gene amplification or insulin-like growth factor 1 receptor (IGF-1R)
expression or activation or various Notch pathway markers. (Dose escalation portion) II. To
perform a preliminary exploratory assessment of whether addition of RO4929097 to erlotinib
leads to tumor shrinkage/response in any tumor deposits that had previously exhibited growth
on erlotinib alone. (Dose escalation portion) III. Conduct a preliminary exploratory
assessment on the expansion cohort with respect to tumor shrinkage/response of the following
over the first 2 cycles of erlotinib and RO4929097 treatment with and without the presence
of mutation, amplification, and activation of markers: tumor IHC scores and RPPA expression
of the Notch ligand jagged 1 (Jag1), and the Notch targets hairy and enhancer of split 1
(HES1), hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1); tumor IHC scores
and RPPA expression of putative stem cell markers cluster of differentiation (CD)24
(decreased in stem cells), CD44, CD133, aldehyde dehydrogenase and of the epithelial to
mesenchymal transition (EMT) markers E-cadherin and vimentin; detectability in tumor of EGFR
T790M mutations, MET amplification, and IGF-1R expression and activation; and soluble
markers of angiogenesis, including stromal cell-derived factor 1 alpha (SDF-1alpha), basic
fibroblastic growth factor (bFGF), cryptic epitope of collagen IV, interleukin (IL)-6, IL-8,
vascular endothelial growth factor (VEGF). (Expansion cohort) IV. We will conduct a
preliminary exploratory assessment of whether percent tumor shrinkage/response or time to
progression correlates with pre-therapy IHC and RPPA expression of Notch 1, 2, 3 and 4, the
above Notch pathway and stem cell markers, with baseline detectability of T790M mutations
and MET amplification, and with baseline IGF-1R expression and activation, and with change
in these markers from the initial biopsy to the subsequent biopsy. (Expansion cohort) V. In
tumor samples collected both during the dose escalation phase and in the expansion cohort,
we will assess if IHC and RPPA expression of Notch, Notch ligand and Notch targets
correlates with expression of stem cell markers.

VI. We will assess if percent tumor shrinkage/response, time to progression and baseline and
change in IHC and RPPA expression of Notch, Notch ligand, Notch targets and stem cell
markers varies with: tumor Notch gene amplification as assessed by fluorescent in situ
hybridization (FISH); tumor IHC and RPPA expression of selected members of the Wnt and
Hedgehog pathways (since these could lead to stem cell properties in cells that do not
express Notch); host (peripheral blood mononuclear cell) polymorphisms for relevant genes in
the Notch pathway; tumor micro ribonucleic acid (RNA) levels.

VII. Trough levels of erlotinib and RO4929097 will be measured in plasma samples of all
patients on the dose-escalation portion of the study approximately 24 hours after the Cycle
1, Day 1 dose and again approximately 24 hours after the Cycle 2, Day 1 dose. These
measurements are being done to permit a preliminary exploratory assessment of whether there
is induction of metabolism of one or both drugs that will lead to decreased drug plasma

VIII. In the Expansion Cohort, plasma levels of erlotinib and RO4929097 will be measured
approximately 24 hours after the Cycle 2, Day 21 erlotinib dose (just prior to initiation of
Cycle 3), and plasma levels of both agents will be measured in plasma approximately 24 hours
after the Cycle 3, Day 1 doses of both agents. These measurements are done to permit a
preliminary exploratory assessment of whether: plasma drug levels correlate with % tumor
shrinkage/response or with change in tumor biomarkers over the first 6 weeks of therapy;
erlotinib plasma concentrations are affected by RO4929097 administration.

OUTLINE: This is a dose-escalation study.

Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21 and
gamma-secretase inhibitor RO4929097 QD on days 1-3, 8-10, and 15-17. Courses repeat every 21
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 weeks.

Inclusion Criteria:

- Dose-escalation portion:

- Patients must have histologically or cytologically confirmed diagnosis of
incurable NSCLC

- Preference will be given to patients with NSCLC who have been treated with
erlotinib, and have either responded initially and then experienced subsequent
growth in one or more tumor deposits while continuing erlotinib (acquired
resistance) or patients who have been treated with erlotinib and failed to
demonstrate any response to it (intrinsic resistance)

- Expansion cohort: patients must satisfy each of the following criteria:

- Histologically or cytologically confirmed non-small cell lung cancer that is
incurable (stage IV or recurrent)

- Patients must not have received prior anti-EGFR therapy

- Patients on both the dose escalation portion of the study and in the Expansion Cohort
portion must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >=
10 mm with computed tomography (CT) scan with cuts at 2.5 or 5 mm

- Patients on both portions of the study must have tumor amenable to core biopsy (or to
incisional, excisional, or punch biopsy) for research purposes

- Any prior anticancer systemic therapy or radiotherapy must have been completed at
least 4 weeks prior to initiation of therapy on this study; (Exception: patients may
be entered within 2 weeks of radiotherapy if the radiotherapy was restricted to femur
below the trochanter, humerus or more distal limb areas)

- Dose escalation portion:

- Unlimited prior therapy is permitted (including prior anti-EGFR therapy), with
the exception that patients who have received prior therapy with a
gamma-secretase inhibitor are not eligible

- Prior therapy is not required

- Preference will be given to NSCLC patients who have been treated with erlotinib
with evidence of acquired or intrinsic resistance to erlotinib

- Expansion cohort:

- Patients may have received an unlimited number of prior systemic regimens for
NSCLC (as adjuvant therapy, as therapy for locally advanced disease or as
therapy for advanced disease) provided they have not received prior anti-EGFR
therapy (small molecule or antibody, etc) or prior gamma-secretase inhibitors

- Prior therapy is not required

- Patients with asymptomatic or minimally symptomatic brain metastases will not be
required to undergo cranial radiation prior to being considered for this trial, and
are eligible provided that it is not anticipated that they will require any of the
following over the course of study treatment:

- Corticosteroids for control of cerebral edema

- Enzyme-inducing anticonvulsants

- Radiotherapy, surgery, or other local therapy for the brain metastases

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets>= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 3 X
institutional upper limit of normal

- Creatinine =< 1.5 X institutional upper limit of normal

- No patients with > grade 1 (by Common Terminology Criteria for Adverse Events [CTCAE]
criteria) hyponatremia or hypocalcemia (based on measurement of ionized calcium)
despite appropriate medical management, no patients with hypophosphatemia (serum
phosphate below the lower limit of normal for the institution, hypomagnesemia (serum
magnesium below the lower limit of normal), or hypokalemia (serum potassium outside
normal limits) despite appropriate medical management

- International normalized ratio (INR) =< 1.7 X upper limit of normal (ULN) and the
patient must not have received aspirin or coumadin and the patient must not have
received aspirin or coumadin within the previous week or a therapeutic dose of a
heparin product within the previous 24 hours

- Fertile patients must use two forms of contraception (i.e., barrier contraception and
one other method of contraception) from at least 2 weeks prior to initiation of
therapy on this study, for the duration of study participation, and for at least 2
months post-treatment; should a woman become pregnant or suspect she is pregnant
while she or her partner are participating in this study and for 2 months after study
participation, the patient should inform the treating physician immediately

- Women of childbearing potential are required to have a negative serum pregnancy
test (with a sensitivity of at least 25 mIU/mL) within 14 days prior to the
first dose of RO4929097 and a negative serum or urine pregnancy test within 24
hours prior to the first dose of RO4929097; following initiation of therapy with
RO4929097, a pregnancy test (serum or urine) will be administered every 3 weeks
while on study; a positive urine test must be confirmed by a serum pregnancy
test; prior to dispensing RO4929097, the investigator or designate must confirm
and document the patient's use of two contraceptive methods, dates of negative
pregnancy test, and confirm the patient's understanding of the teratogenic
potential of RO4929097

- Patients with lung cancer may have false-positive pregnancy tests due to
production of beta-human chorionic gonadotropin (HCG) by tumor; patients with a
positive pregnancy test who are unlikely to be pregnant may be considered for
entry on this trial if they are deemed to be unlikely to be pregnant by an
obstetrician or gynecologist and if the study sponsor is in agreement with their
study entry

- Female patients of childbearing potential are defined as patients who do not
fall into either of the categories listed above and to whom any of the following

- Patients with regular menses

- Patients, after menarche with amenorrhea, irregular cycles, or using a
contraceptive method that precludes withdrawal bleeding

- Women who have had tubal ligation

- Female patients may be considered to NOT be of childbearing potential for the
following reasons:

- The patient has undergone total abdominal hysterectomy with bilateral
salpingo-oophorectomy or bilateral oophorectomy

- The patient is medically confirmed to be menopausal (no menstrual period)
for 34 consecutive months

- Men participating in the study must also use 2 methods of contraception including 1
barrier method from the time of initiation of therapy on the study until 2 months
after their last treatment on the study if their sexual partner has childbearing
potential; if their sexual partner is already pregnant, 1 barrier method must be used
to minimize the probability of exposure of the fetus to potentially toxic
concentrations of RO4929097

- Breastfeeding should be discontinued if the mother is treated with RO4929097

- Able to swallow oral medications

- No malabsorption syndrome or other condition that would interfere with intestinal

- No diarrhea > grade 1 despite appropriate therapy

- No uncontrolled concurrent illness including, but not limited to, any of the

- Ongoing or active infection requiring systemic therapy (with antibiotics or
antiviral or antifungal agents)

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Angina at rest

- A history of torsades de pointes

- Potentially life-threatening cardiac arrhythmias, however patients with any of
the following are eligible:

- Chronic, stable atrial fibrillation

- Premature atrial or ventricular contractions

- Sinus tachycardia, provided the rate is controlled at < 115 per minute

- Sinus bradycardia, provided the rate is > 50 per minute

- Myocardial infarction within the past 3 months

- Psychiatric illness or social situations that would limit compliance with study

- Baseline QTcF =< 450 msec (for male patients) or =< 470 msec (for female patients)

- No patients requiring drugs that are known to cause torsades de pointes and/or
prolonged QTc intervals

- Patients requiring drugs with a possible but unproven association with torsades
de pointes and/or QTc prolongation may be eligible, but will require additional
electrocardiogram assessments

- No known serologic positivity for hepatitis A, B, or C

- No HIV-positive patients requiring combination antiretroviral therapy

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to RO4929097, OSI-774, or other agents used in this study

- Recovered from toxicities (of CTCAE > grade 2) from prior therapy

- No prior anti-EGFR therapy (small molecule tyrosine kinase inhibitor [TKI] or
antibody) (expansion phase only); NOTE: This in contrast to the dose-escalation
portion of the study in which patients with prior anti-EGFR therapy will be eligible

- At least 4 weeks since prior anticancer systemic therapy or radiotherapy (2 weeks for
radiotherapy that was restricted to distal limbs such as femur below the trochanter,
humerus, or more distal limb areas)

- Patients in the dose-escalation portion who have previously received erlotinib
may start therapy on this trial as early as 1 week after stopping prior

- No other concurrent investigational agents

- No concurrent medications (other than erlotinib hydrochloride) that are strong
inducers/inhibitors or substrates of CYP3A4

- No concurrent medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin)

- No concurrent medications or food that may interfere with the metabolism of
gamma-secretase inhibitor RO4929097 (RO4929097) or erlotinib hydrochloride, including
ketoconazole, grapefruit, and grapefruit juice

- No other concurrent anticancer agent or therapy

- No pregnant women

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum-tolerated dose of gamma-secretase inhibitor RO4929097 and erlotinib hydrochloride (Dose escalation phase)

Outcome Time Frame:

At least 3 weeks after day 1 of course 1

Safety Issue:


Principal Investigator

Don Gibbons

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

August 2010

Completion Date:

Related Keywords:

  • Recurrent Non-Small Cell Lung Cancer
  • Stage IV Non-Small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



M D Anderson Cancer Center Houston, Texas  77030