Erlotinib Hydrochloride and Onalespib Lactate in Treating Patients With Recurrent or Metastatic EGFR-Mutant Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of erlotinib hydrochloride (erlotinib) and
onalespib lactate (onalespib) in patients with EGFR-mutant non-small cell lung cancer
(NSCLC). (PHASE I) II. To preliminarily assess efficacy of combination erlotinib and
onalespib at the recommended phase II dose (RP2D) determined in the phase I portion of the
study in EGFR-mutant NSCLC patients who have not had a complete or partial response by
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 to frontline erlotinib after a
minimum of 12 weeks on erlotinib. (PHASE II, COHORT A) III. To preliminarily assess efficacy
of combination erlotinib and onalespib at the RP2D in NSCLC patients whose tumor harbors an
EGFR exon 20 insertion (an EGFR mutation not typically responsive to single agent erlotinib).
(PHASE II, COHORT B)

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity (primary aim phase II, secondary aim phase I).

II. To evaluate in a preliminary manner the progression-free survival (PFS) and disease
control rate (DCR) of patients treated with erlotinib/onalespib.

III. To characterize the pharmacokinetics of the above drug combinations at the recommended
phase II dose (RP2D).

TERTIARY OBJECTIVES:

I. To explore plasma EGFR-mutant deoxyribonucleic acid (DNA) as a biomarker by detecting
changes in plasma EGFR-mutant DNA levels (including plasma EGFR-T790M) and new mutations that
may represent resistance to treatment.

II. To demonstrate knockdown of Hsp90 client oncoproteins via treatment with erlotinib and
onalespib by multiplexed immunofluorescence in serial tumor biopsies.

III. To establish patient derived xenotransplant models in EGFR-mutated NSCLC with a focus on
tumors that lack response to single agent erlotinib and in patients with tumors harboring
EGFR exon 20 insertions.

OUTLINE: This is a phase I, dose-escalation study of onalespib lactate followed by a phase II
study.

Patients receive erlotinib hydrochloride orally (PO) daily and onalespib lactate
intravenously (IV) over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for at
least 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 1 year and
then annually thereafter.

Inclusion Criteria:

- PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that
harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X,
exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine
kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically
confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on
platinum containing chemotherapy

- PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed
NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon
18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on
erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive
disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of
treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of
initiation of erlotinib

- PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed
NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after
platinum doublet chemotherapy

- FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient
does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other
EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and
onalespib

- FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent,
erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and
onalespib; last dose of erlotinib must be less than 28 days from when patient signs
consent

- FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib
is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does
NOT need to be discontinued prior to initiation of erlotinib and onalespib

- Local testing for EGFR-mutations for this study is acceptable provided it was
performed in a Clinical Laboratory Improvement Act (CLIA) certified lab

- Patients with a prior history of brain metastases are eligible provided:

- The brain metastases have been treated

- The patient is asymptomatic from the brain metastases

- Corticosteroids prescribed for the management of brain metastases have been
discontinued at least 7 days prior to registration

- Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks
prior to receiving study drugs

- Patients must have recovered from adverse events attributable to previous treatment to
=< grade 1, except for alopecia and sensory neuropathy =< grade 2

- Measurable disease by RECIST 1.1

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) < 1.3 upper limit of normal (ULN)

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation; should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately; men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of erlotinib and/or onalespib
administration

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who are receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to erlotinib and/or onalespib

- History of pneumonitis attributed to an EGFR inhibitor; history of radiation
pneumonitis is allowed provided steroid administration for pneumonitis was not
required

- Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec

- Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or
multigated acquisition scan (MUGA)

- Drugs that are known to increase torsades de pointes should be avoided; patients must
discontinue these medications prior to enrollment on study; selection of alternate
concomitant medications with no or minimal torsades de pointes potential is
recommended

- Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate
concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is
recommended; as part of the enrollment/informed consent procedures, the patient will
be counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the patient is considering a new
over-the-counter medicine or herbal product

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with erlotinib and onalespib

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Prior treatment with a Hsp90 inhibitor

- Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment
with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib
must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours
before the next dose of the H2-receptor antagonist; although the effect of antacids on
erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib
dose should be separated by several hours, if an antacid is necessary

- Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's
syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp
examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal
corneal sensitivity test (Schirmer test or similar tear production test)