Adenosquamous Lung Carcinoma, Bronchioloalveolar Carcinoma, Large Cell Lung Carcinoma, Lung Adenocarcinoma, Recurrent Non-Small Cell Lung Carcinoma, Squamous Cell Lung Carcinoma
Conditions
Brief summary
This phase II trial studies the side effects and how well Akt inhibitor MK2206 (MK2206) and erlotinib hydrochloride works in treating patients with advanced non-small cell lung cancer who have progressed after previous response to erlotinib hydrochloride therapy. MK2206 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the efficacy (with the primary endpoint of disease control at 12 weeks) and tolerability of the combination of MK2206 plus erlotinib (erlotinib hydrochloride) in previously erlotinib-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-treated patients with NSCLC who are treated with MK2206 plus erlotinib. II. To determine the overall survival of previously erlotinib-treated patients with NSCLC who are treated with MK2206 plus erlotinib. III. To assess the toxicity experienced by previously erlotinib-treated patients with NSCLC treated with MK2206 plus erlotinib. 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-treated patients with NSCLC treated with MK2206 plus erlotinib. OUTLINE: Patients receive Akt inhibitor MK2206 orally (PO) every other day (QOD) 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. After completion of study therapy, patients are followed up every 12 weeks for one year and then annually thereafter.
Interventions
DRUGAkt Inhibitor MK2206
Given PO
DRUGErlotinib Hydrochloride
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically or cytologically confirmed non-small cell lung cancer of any histologic subtype * NOTE: 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; however, 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 radiologic or clinical progressive disease following prior benefit (response or stable disease) to EGFR-tyrosine kinase inhibitor (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 aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate 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 * 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; 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 metastases (mets) have been stopped for at least 14 days * History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 or erlotinib * Caution must be observed for patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (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 corrected QT (QTc) interval during MK-2206 treatment; prolongation of QTc interval is potentially a safety concern while on MK-2206 therapy; cardiovascular: baseline Fridericia QT (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; breastfeeding should be discontinued if the mother is treated with this combination * Human immunodeficiency (HIV)-positive patients on combination antiretroviral therapy are ineligible * 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-control Rate | At 12 weeks | Disease-control rate defined as response rate + stable disease at 12 weeks. Stable disease must have been achieved for 12 weeks or longer. Response evaluated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. |
| Objective Response | Up to 2 years | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response = CR + PR |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-free Survival | Up to 2 years | Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Time Frame: Up to 2 years | Toxicities of Grade 3 or higher Attributed to Akt inhibitor MK2206 plus erlotinib hydrochloride, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 |
| Median Overall Survival | Up to 2 Years | Estimated using the product-limit method of Kaplan and Meier. Event defined as death due to any cause. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| EGFR-Mutated Tumors Patients with EGFR-mutated tumors. | 45 |
| EGFR Wild-Type Tumors Patients with EGFR wild-type tumors. | 35 |
| Total | 80 |
Baseline characteristics
| Characteristic | EGFR-Mutated Tumors | Total | EGFR Wild-Type Tumors |
|---|---|---|---|
| Age, Continuous | 64 years | 64 years | 63 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 21 Participants | 27 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) White | 20 Participants | 47 Participants | 27 Participants |
| Region of Enrollment United States | 45 participants | 80 participants | 35 participants |
| Sex: Female, Male Female | 31 Participants | 51 Participants | 20 Participants |
| Sex: Female, Male Male | 14 Participants | 29 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 45 / 45 | 35 / 35 |
| serious Total, serious adverse events | 17 / 45 | 21 / 35 |
Outcome results
Primary
Disease-control Rate
Disease-control rate defined as response rate + stable disease at 12 weeks. Stable disease must have been achieved for 12 weeks or longer. Response evaluated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.
Time frame: At 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EGFR-Mutated Tumors | Disease-control Rate | 40 percentage of subjects |
| EGFR Wild-Type Tumors | Disease-control Rate | 43 percentage of subjects |
Primary
Objective Response
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response = CR + PR
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EGFR-Mutated Tumors | Objective Response | 9 percentage of subjects |
| EGFR Wild-Type Tumors | Objective Response | 3 percentage of subjects |
Secondary
Median Overall Survival
Estimated using the product-limit method of Kaplan and Meier. Event defined as death due to any cause.
Time frame: Up to 2 Years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EGFR-Mutated Tumors | Median Overall Survival | 10.6 Months |
| EGFR Wild-Type Tumors | Median Overall Survival | 11.1 Months |
Secondary
Median Progression-free Survival
Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EGFR-Mutated Tumors | Median Progression-free Survival | 4.4 Months |
| EGFR Wild-Type Tumors | Median Progression-free Survival | 4.6 Months |
Secondary
Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride
Toxicities of Grade 3 or higher Attributed to Akt inhibitor MK2206 plus erlotinib hydrochloride, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time frame: Time Frame: Up to 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Erythema multiforme | 1 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Anemia | 0 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Mucositis | 4 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Nausea | 1 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Vomiting | 0 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Fatigue | 5 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Lung infection | 2 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Urinary tract infection | 1 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Creatinine increased | 0 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Lymphocyte count decreased | 6 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Dehydration | 3 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Hyperglycemia | 3 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Hypokalemia | 2 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Hyponatremia | 0 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Hypophophatemia | 1 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Skin peeling (feet) | 0 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Pruritus | 0 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Rash | 9 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Hypertension | 1 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Skin infection | 0 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Anorexia | 0 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Myalgia | 1 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Neoplasm | 0 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Dyspnea | 1 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Dry skin | 0 participants |
| EGFR-Mutated Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Diarrhea | 5 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Fatigue | 3 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Hyponatremia | 2 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Anemia | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Diarrhea | 5 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Dyspnea | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Mucositis | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Hypophophatemia | 0 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Nausea | 2 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Erythema multiforme | 0 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Vomiting | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Neoplasm | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Skin infection | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Skin peeling (feet) | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Lung infection | 0 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Anorexia | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Urinary tract infection | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Pruritus | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Creatinine increased | 1 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Dry skin | 3 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Lymphocyte count decreased | 3 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Rash | 3 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Dehydration | 0 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Myalgia | 0 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Hyperglycemia | 0 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Hypertension | 0 participants |
| EGFR Wild-Type Tumors | Toxicity of Akt Inhibitor MK2206 Plus Erlotinib Hydrochloride | Hypokalemia | 0 participants |