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Phase II Trial of the Akt Inhibitor MK-2206 Plus Erlotinib (OSI-774) in Patients With Advanced Non-Small Cell Lung Cancer Who Have Progressed After Previous Response (Including Stable Disease) With Erlotinib Therapy


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Adenocarcinoma of the Lung, Adenosquamous Cell Lung Cancer, Bronchoalveolar Cell Lung Cancer, Large Cell Lung Cancer, Recurrent Non-small Cell Lung Cancer, Squamous Cell Lung Cancer

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Trial Information

Phase II Trial of the Akt Inhibitor MK-2206 Plus Erlotinib (OSI-774) in Patients With Advanced Non-Small Cell Lung Cancer Who Have Progressed After Previous Response (Including Stable Disease) With Erlotinib Therapy


PRIMARY OBJECTIVES:

I. To evaluate the efficacy (with the primary endpoint of disease control at 12 weeks) and
tolerability of the combination of Akt inhibitor MK2206 (MK2206) plus erlotinib
hydrochloride in previously erlotinib hydrochloride-treated patients with recurrent or
progressive advanced non-small cell lung cancer (NSCLC) whose tumors are either epidermal
growth factor receptor (EGFR) mutated or EGFR wild-type.

SECONDARY OBJECTIVES:

I. To determine progression-free survival of previously erlotinib hydrochloride-treated
patients with NSCLC who are treated with MK2206 plus erlotinib hydrochloride. II. To
determine the overall survival of previously erlotinib hydrochloride-treated patients with
NSCLC who are treated with MK2206 plus erlotinib hydrochloride.

III. To assess the toxicity experienced by previously erlotinib hydrochloride-treated
patients with NSCLC treated with MK2206 plus erlotinib hydrochloride. IV. To perform
correlative analysis of tumor biomarkers to assess, in a preliminary manner, the association
between tumor mutations and/or abnormalities and clinical outcome of previously erlotinib
hydrochloride-treated patients with NSCLC treated with MK2206 plus erlotinib hydrochloride.

OUTLINE: This is a multicenter study. Patients are stratified according to epidermal growth
factor receptor (EGFR) status (mutated vs wild-type).

Patients receive Akt inhibitor MK2206 orally (PO) every other day of a 28-day course, and
erlotinib hydrochloride PO once daily (QD) on days 1-28. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

Some patients undergo blood sample collection at baseline and periodically during study for
pharmacokinetics and correlative studies.

After completion of study therapy, patients are followed up every 12 weeks for one year then
annually thereafter.


Inclusion Criteria:



- Patients must have histologically or cytologically confirmed non-small cell lung
cancer (NSCLC) of any histologic subtype

- Epidermal growth factor receptor (EGFR) mutational status (either wild-type or
positive for an activating mutation)will be determined for all patients on this
study

- Commercial assays for EGFR mutation status are allowed

- Knowledge of EGFR mutational status is not required at the time of protocol
entry but should be determined or known before the end of course 2

- If one of the strata is temporarily closed to accrual, knowledge of EGFR
mutational status will be required prior to protocol entry

- Patients may have measurable or non-measurable disease; x-rays and/or scans for
disease assessment of measurable disease must have been completed within 28 days
prior to registration

- Patients must have radiological or clinical progressive disease following prior
benefit(response or stable disease) to EGFR-TKI therapy (e.g., erlotinib
hydrochloride) administered either as a single agent or in combination with other
agents for at least 12 weeks prior to progression

- Patients may have received intervening systemic therapy after EGFR-TKI
progression

- Patients must have radiologic or clinical progressive disease following prior benefit
(response or stable disease) to EGFR-TKI therapy (e.g., erlotinib) administered
either as a single agent or in combination with other agents for at least 12 weeks
prior to progression; (Note: patients may have received intervening systemic therapy
after EGFR-TKI progression); additionally, patients must have documentation of
radiographic progression within the preceding three months prior to study entry

- Prior cytotoxic chemotherapy is allowed; any number of prior chemotherapy regimens is
also allowed; prior cetuximab therapy is also allowed; NOTE: a patient with an EGFR
activating mutation who has received EGFR-TKI therapy as first line therapy, but has
not received platinum-based chemotherapy, would be considered eligible for this trial

- Karnofsky performance status >= 60%

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Total bilirubin =< upper institutional normal limits

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

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

- Prior to the first patient registration, this study must be institutional review
board approved; a copy of the institutional review board (IRB) approval for each site
involved must be given to the Data Coordinating Center at City of Hope

- The effects of MK-2206 on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because MK-2206 or erlotinib have the potential
to be teratogenic, women of childbearing potential and men must use two forms of
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, the patient should inform the treating physician immediately

- Patients on coumadin should have their International Normalized Ratio (INR) monitored
at least once per week or more frequently depending on the investigator's judgment;
there have been some case reports of increased INR when coumadin is co-administered
with erlotinib

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

- Patients should have tumor tissue (either fresh frozen tumor tissue or
paraffin-embedded tumor tissue) available for retrieval; if an endobronchial lesion
is present or suspected, bronchoscopy is recommended as a source of fresh tissue;
tissue blocks or unstained slides from the time of original diagnosis are acceptable
if repeat biopsy is not feasible

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have any
ongoing Grade 2 or greater toxicity from a prior treatment

- Patients may not be receiving any other investigational agents

- Patients with symptomatic brain metastases should be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events; patients with asymptomatic controlled or treated (e.g., with
radiation and/or surgery) brain metastases are otherwise eligible as long as
corticosteroids given expressly for brain mets have been stopped for at least 14 days

- Caution must be observed for patients receiving any medications or substances that
are strong inhibitors or inducers of CYP 450 3A4; although these patients are still
potentially eligible, close monitoring is required for toxicity

- Preclinical studies demonstrated the potential of MK-2206 for induction of
hyperglycemia in all preclinical species tested; patients with diabetes or in risk
for hyperglycemia should not be excluded from trials with MK-2206, but the
hyperglycemia should be well controlled on oral agents before the patient enters the
trial

- Preclinical studies indicated transient changes in QTc interval during MK-2206
treatment; prolongation of QTc interval is potentially a safety concern while on
MK-2206 therapy; cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec
(female) will exclude patients from entry on study

- 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 because MK-2206 and erlotinib are
anti-cancer agents with the potential for teratogenic or abortifacient effects;
because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with MK-2206 and erlotinib, breastfeeding should
be discontinued if the mother is treated with this combination

- Human immunodeficiency (HIV)-positive patients on combination antiretroviral therapy
are ineligible because of the potential for pharmacokinetic interactions with MK-2206
plus erlotinib; in addition, these patients are at increased risk of lethal
infections when treated with marrow-suppressive therapy; appropriate studies will be
undertaken in patients receiving combination antiretroviral therapy when indicated

- Prior MK-2206 therapy is not allowed

- Patients unable to swallow MK-2206 tablets and erlotinib tables whole are ineligible;
(the tablets cannot be crushed or broken)

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Objective response of patients with EGFR mutation as defined by RECIST (stratum 1)

Outcome Time Frame:

Up to 2 years

Safety Issue:

No

Principal Investigator

Primo Lara

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beckman Research Institute

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02578

NCT ID:

NCT01294306

Start Date:

February 2011

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Lung
  • Adenosquamous Cell Lung Cancer
  • Bronchoalveolar Cell Lung Cancer
  • Large Cell Lung Cancer
  • Recurrent Non-Small Cell Lung Cancer
  • Squamous Cell Lung Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Adenocarcinoma, Bronchiolo-Alveolar
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms

Name

Location

City of Hope Medical CenterDuarte, California  91010
University of PittsburghPittsburgh, Pennsylvania  15261
Tower Cancer Research FoundationBeverly Hills, California  90211
UC Davis Comprehensive Cancer CenterSacramento, California  95817
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
University of Southern CaliforniaLos Angeles, California  90033
Penn State Milton S Hershey Medical CenterHershey, Pennsylvania  17033