Carcinoma, Non-Small-Cell LungPhase 2NCT01306045

Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies

A Phase 2 study testing AZD6244, MK-2206 and Lapatinib in people with Carcinoma, Non-Small-Cell Lung and Carcinoma, Small Cell Lung, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

Search all trials

Trial summary

Background: The current standard of care for advanced lung cancer and cancers of the thymus consists primarily of chemotherapy treatment. The drugs used for chemotherapy depend on the classification of the cancer in different categories that are based on the appearance of the cancer in the microscope. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Carcinoma, Non-Small-Cell Lung, Carcinoma, Small Cell Lung, Carcinoma, Thymic
What is being tested?: AZD6244, MK-2206 and Lapatinib
Type of treatment: Pill or oral medicine, Surgery or procedure
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 647 participants
Where: 1 siteUnited States
Study dates: 8 Feb 2011to 17 Jul 2024
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

None listed.

Who cannot join

Patients who have had major surgery, chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.
Patients may not be receiving any other investigational agents or other medications for the treatment of their malignancy.
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. However, patients who have had treatment for their brain metastases and whose brain metastatic disease status has remained stable for at least 1 week after the end of brain radiation may be enrolled to undergo molecular profiling at the discretion of the principal investigator. In addition, brain metastatic disease should be stable for at least 4 weeks, before the patients can be enrolled in any of the experimental treatment arms.
Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain tablets are excluded.
Any uncontrolled medical illness that precludes the patient from undergoing a biopsy for molecular profiling and/or receiving treatment under one of the experimental arms of the study should be excluded. These conditions include but are not limited to:
Ongoing or uncontrolled, symptomatic congestive heart failure (Class III or IV as defined by the New York Heart Association (NYHA) functional classification system (see Appendix D).

Show all 16Show fewer

Uncontrolled hypertension
Unstable angina pectoris
Cardiac arrhythmia
Uncontrolled diabetes
Uncontrolled psychiatric illness/social situations that would limit compliance with study requirements.
Patients with corrected QT interval (QTc) prolongation (defined as a QTc interval equal to or greater than 500 msec) or other significant electrocardiogram (ECG) abnormalities are excluded.
Caution should be used if patients are required to use a concomitant medication that can prolong the Q wave T wave (QT) interval and efforts should be made to switch to a different medication before the patient begins treatment under an experimental arm. See Appendix E for a table of medications with the potential to prolong the QTc interval. A comprehensive list of agents with the potential to cause QTc prolongation can be found at: http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm
The eligibility of patients taking medications that are potent inducers or inhibitors of that enzyme will be determined following a review of their case by the Principal Investigator. (A list of potent Cytochrome P450 3A4 (CYP3A4) inducers or inhibitors can be found in Appendix F). Every effort should be made to switch patients taking such agents or substances to other medications before they begin treatment with one of the experimental drug included in this protocol, particularly patients with gliomas or brain metastases who are taking enzyme-inducing anticonvulsant agents. A comprehensive list of medications and substances known or with the potential to alter the pharmacokinetics of sunitinib through CYP3A4 is provided in Appendix F.
Patients with tumor amenable to potentially curative therapy as assessed by the investigator.
Pregnant women are excluded from this study because many of the Food and Drug Administration (FDA) approved agents and investigational agents in this trial have 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 these agents, breastfeeding should be discontinued if the mother is treated in this protocol. These potential risks may also apply to other agents used in this study.

Trial locations and contacts

1 site in 1 country.

United States1 site

National Institutes of Health Clinical Center
Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Pilot Trial of Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies

Background:

The current standard of care for advanced lung cancer and cancers of the thymus consists primarily of chemotherapy treatment. The drugs used for chemotherapy depend on the classification of the cancer in different categories that are based on the appearance of the cancer in the microscope. Though this approach has been proved to be useful in some ways, the survival rates of individuals with lung cancer and cancers of the thymus are still very poor. Recent research has shown that several genetic abnormalities play an important role in the development and growth of lung cancer and cancers of the thymus, and that it is possible to improve treatment success rates with drugs that specifically target some of the abnormal genes. Researchers are interested in determining whether it is possible to analyze the genes of patients with lung cancer and cancers of the thymus in order to provide personalized treatment with drugs that target the specific gene abnormalities.

Objectives:

To evaluate the effectiveness of genetic analysis in determining targeted therapy for individuals with advanced non-small cell lung cancer, small cell lung cancer, and thymic cancer.

Eligibility:

Individuals at least 18 years of age who have been diagnosed with either lung cancer or a cancer of the thymus that is not considered to be curable with the use of surgery or radiation therapy.

Design:

Participants will be screened with a full medical history and physical examination, blood and urine tests, and tumor imaging studies. Participants will have a tumor biopsy or provide previously collected tumor tissue for study.
Based on the results of the tumor biopsy study, participants will be separated into different treatment groups:
Participants with epidermal growth factor receptor (EGFR) gene mutation will receive a drug called erlotinib, which inhibits a protein called EGFR that is thought to be a key factor in the development and progression of some cancers.
Participants with Kirsten rat sarcoma virus (KRAS), proto-oncogene B-Raf (BRAF), Harvey Rat sarcoma virus (HRAS), or NRAF gene mutations will receive a drug called AZD6244, which inhibits a protein called methyl ethyl ketone (MEK) that is thought to be a key factor in the development and progression of some cancers.
Participants with phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), protein kinase B (AKT), or phosphatase and tensin homolog (PTEN) gene mutations will receive a drug called MK-2206, which inhibits a protein called AKT that is thought to be a key factor in the development and progression of some cancers.
Participants with KIT or platelet-derived growth factor receptor A, (PDGFRA) gene mutations will receive a drug called sunitinib, which inhibits some proteins that are thought to be key factors in the development and progression of some cancers, including kidney cancer.
Participants who have -erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene mutation or amplification will receive a drug called lapatinib, which inhibits some proteins that are thought to be key factors in the development and progression of some cancers, including breast cancer.
Participants who do not have any of the genetic abnormalities described above will be offered different options for treatment, including standard of care chemotherapy or treatment with investigational agents in a different research protocol.
After 6 weeks of treatment, participants will have imaging studies to evaluate the status of their cancer. Treatment will continue as long as participants tolerate the drugs, and the disease does not progress.
Participants who benefit from the first treatment but eventually develop resistance and progression of their cancer will be offered the chance to have a second tumor biopsy and undergo a different treatment for their cancer.

Read the detailed description

BACKGROUND:

A better understanding of the genetic make-up of the individual tumor may offer potentially improved therapies. This approach may also give rapid access to response data in patients with sometimes rare genetic abnormalities.
In addition, it will allow us to test targeted therapies in a select population of patients that is more likely to have a favorable response based on their molecular profile and the specific mechanism of action of the drug being tested.
This approach will also speed up drug development and potentially approval and rescue an otherwise ineffective drug candidate for the specific subgroup that can benefit.

Primary Objectives:

To determine the feasibility of the use of tumors molecular profiling and targeted therapies in the treatment of advanced stage non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and thymic malignancies.
To estimate the response rate of molecular profile directed treatments in NSCLC, SCLC and thymic malignancies patients.

ELIGIBILITY:

Patients with histologically confirmed advanced lung cancer or thymic malignancies for whom surgical resection with curative intent is not feasible.
Patients must either have biopsiable disease and be willing to undergo biopsy for molecular profiling or have paraffin embedded tissue blocks suitable for molecular profiling analysis.
Individuals are eligible for epidermal growth factor receptor (EGFR) germline mutation testing if they have:
a personal history of invasive lung cancer or one of the pre-invasive histologies associated with the development of lung cancer and more than two affected family members with invasive lung cancer or one of the pre-invasive histologies associated with the development of lung cancer,

a first-degree relative with a known EGFR germline mutation (EGFR exon 20 T790M, exon 21 V843I, exon 21 R831C and exon 20 R776G).

DESIGN:

All patients will have their tumors undergo molecular profiling. Based on these results and on other eligibility criteria, the patients will be offered enrollment into different targeted therapy arms.
At the NCI site only, individuals eligible for EGFR germline mutation will undergo testing for germline mutations affecting the EGFR gene; if a mutation is detected, their first-degree relatives would be invited to undergo testing for the index germline mutation found in the proband and appropriate follow-up on trial.
Effective with Amendment I, the participating site, Oregon Health and Science University (OHSU), will discontinue new enrollments and data entry for existing patients on the Not Other Specified (NOS) arm on this protocol in favor of the OHSU protocol L8639, Personalized Cancer Medicine Registry. The data from these patients will be included with the data from 11-C-0096 (8639) National Cancer Institute (NCI) patients at the time of publication. Any OHSU patients who are eligible for a treatment arm will continue to be enrolled and followed per protocol.

Conditions: Carcinoma, Non-Small-Cell Lung, Carcinoma, Small Cell Lung, Carcinoma, Thymic
Being tested: AZD6244, MK-2206, Lapatinib, Erlotinib, Sunitinib
Keywords: AZD6244, MK-2206, Lapatinib, Erlotinib, Sunitinib
Medical subject headings: Carcinoma, Non-Small-Cell Lung, Small Cell Lung Carcinoma, Thymoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

AZD6244Drug
Also called Selumetinib
Cycle = 21 days AZD6244 Hydrogen Sulfate 75 mg by mouth (PO) every (Q) 12 Hours
MK-2206Drug
Cycle = 28 days MK-2206 200 mg by mouth (PO) every (Q) Week
LapatinibDrug
Also called Tykerb
Cycle = 21 days Lapatinib 1500 mg by mouth (PO) every day (QD)
ErlotinibDrug
Also called Tarceva
Cycle = 21 days Erlotinib 150 mg by mouth (PO) every morning (QAM)
SunitinibDrug
Also called Sutent
Cycle = 42 days Sunitinib 50 mg by mouth (PO) on days 1-28
Molecular ProfilingProcedure or surgery
Molecular profiling of tumor tissue. Not Otherwise Specified (NOS) arm. Participants who do not meet the eligibility criteria for enrollment or who meet eligibility criteria for a particular arm but can't be enrolled

Study groups in NCT01306045
Study group	Role	What they receive
A/ Erlotinib	Active comparator	Arm A - Erlotinib 150 mg by mouth (PO) every morning (QAM) Receives: Drug: Erlotinib; Procedure: Molecular Profiling
B/ AZD6244	Active comparator	AZD6244 Hydrogen Sulfate 75 mg by mouth (PO) every (Q) 12 Hours Receives: Drug: AZD6244; Procedure: Molecular Profiling
C/ MK-2206	Active comparator	MK-2206 200 mg by mouth (PO) every (Q) Week Receives: Drug: MK-2206; Procedure: Molecular Profiling
D/ Lapatinib	Active comparator	Lapatinib 1500 mg by mouth (PO) every day (QD) Receives: Drug: Lapatinib; Procedure: Molecular Profiling
E/Sunitinib	Active comparator	Sunitinib 50 mg by mouth (PO) on days 1-28 Receives: Drug: Sunitinib; Procedure: Molecular Profiling
F/ Not Otherwise Specified (NOS)	Other	Participants who do not meet the eligibility criteria for enrollment Receives: Procedure: Molecular Profiling

What is being measured

The primary outcome is the main question the study is designed to answer.

Percentage of Enrolled Participants Testing Positive for Genomic Abnormality
To determine the feasibility of the use of tumor molecular profiling and targeted therapies in the treatment of Non-Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), and Thymic Malignancies, the trial will be evaluated by determining the percentage of enrolled participants with a genomic abnormality. Identifying molecular profiles may help identify new targeted treatments for cancer.
Measured: 1 year and 11 months
Number of Evaluable Participants With a Response Based on Molecular Profile Directed Treatments in Non-Small Cell Lung Cancer, (NSCLC), Small Cell Lung Cancer (SCLC), and Thymic Malignancies
Efficacy will be determined by assessing if participants who have treatment assigned on the basis of their molecular profiling results will exhibit reasonable response to the drug selected for their particular profile. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study Progressive Disease (PD) is At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.
Measured: 1 year and 13 months
Percentage of Evaluable Participants Overall Response Rate (ORR) Based on the Drug Selected for Their Particular Profile
Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).Partial Response (PD) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study Progressive Disease (PD) is At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.
Measured: 1 year and 13 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

8 Feb 201117 Jul 2024

First posted1 Mar 2011 (estimated)
Study start8 Feb 2011
Primary completion12 Feb 2014
Study completion17 Jul 2024

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (5)Papers the sponsor has linked to this study.
Other trials for Carcinoma, Non-Small-Cell LungStudies of the same condition, open and under way.
More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 647 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01306045
Sponsor's protocol ID: 110096
Other IDs: 11-C-0096
Status last verified: Sep 2024
First submitted: 26 Feb 2011
Last updated: 1 Oct 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: All Individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Publications

Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, Hanson LJ, Gore L, Chow L, Leong S, Maloney L, Gordon G, Simmons H, Marlow A, Litwiler K, Brown S, Poch G, Kane K, Haney J, Eckhardt SG. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008 May 1;26(13):2139-46. doi: 10.1200/JCO.2007.14.4956. Epub 2008 Apr 7.
PubMed 18390968
Allen LF, Sebolt-Leopold J, Meyer MB. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol. 2003 Oct;30(5 Suppl 16):105-16. doi: 10.1053/j.seminoncol.2003.08.012.
PubMed 14613031
Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005 Nov 14;24(50):7455-64. doi: 10.1038/sj.onc.1209085.
PubMed 16288292
Thomas A, Chen Y, Steinberg SM, Luo J, Pack S, Raffeld M, Abdullaev Z, Alewine C, Rajan A, Giaccone G, Pastan I, Miettinen M, Hassan R. High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis. Oncotarget. 2015 May 10;6(13):11694-703. doi: 10.18632/oncotarget.3429.
PubMed 26028668
Lopez-Chavez A, Thomas A, Rajan A, Raffeld M, Morrow B, Kelly R, Carter CA, Guha U, Killian K, Lau CC, Abdullaev Z, Xi L, Pack S, Meltzer PS, Corless CL, Sandler A, Beadling C, Warrick A, Liewehr DJ, Steinberg SM, Berman A, Doyle A, Szabo E, Wang Y, Giaccone G. Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol. 2015 Mar 20;33(9):1000-7. doi: 10.1200/JCO.2014.58.2007. Epub 2015 Feb 9.
PubMed 25667274

Study at a glance

From the registry record, last updated by the sponsor on 1 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Pilot Trial of Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies
ClinicalTrials.gov ID: NCT01306045
Acronym / sponsor ID: 110096
Conditions: Carcinoma, Non-Small-Cell Lung, Carcinoma, Small Cell Lung, Carcinoma, Thymic
Keywords: AZD6244, MK-2206, Lapatinib, Erlotinib, Sunitinib
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 647 participants (actual)
Lead sponsor: National Cancer Institute (NCI)US National Institutes of Health
Study start: 8 Feb 2011 (actual)
Primary completion: 12 Feb 2014 (actual)
Study completion: 17 Jul 2024 (actual)
First posted: 1 Mar 2011 (estimated)
Results: Posted 11 Apr 2023

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Background:

The current standard of care for advanced lung cancer and cancers of the thymus consists primarily of chemotherapy treatment. The drugs used for chemotherapy depend on the classification of the cancer in different categories that are based on the appearance of the cancer in the microscope. Though this approach has been proved to be useful in some ways, the survival rates of individuals with lung cancer and cancers of the thymus are still very poor. Recent research has shown that several genetic abnormalities play an important role in the development and growth of lung cancer and cancers of the thymus, and that it is possible to improve treatment success rates with drugs that specifically target some of the abnormal genes. Researchers are interested in determining whether it is possible to analyze the genes of patients with lung cancer and cancers of the thymus in order to provide personalized treatment with drugs that target the specific gene abnormalities.

Objectives:

To evaluate the effectiveness of genetic analysis in determining targeted therapy for individuals with advanced non-small cell lung cancer, small cell lung cancer, and thymic cancer.

Eligibility:

Individuals at least 18 years of age who have been diagnosed with either lung cancer or a cancer of the thymus that is not considered to be curable with the use of surgery or radiation therapy.

Design:

Participants will be screened with a full medical history and physical examination, blood and urine tests, and tumor imaging studies. Participants will have a tumor biopsy or provide previously collected tumor tissue for study.
Based on the results of the tumor biopsy study, participants will be separated into different treatment groups:
Participants with epidermal growth factor receptor (EGFR) gene mutation will receive a drug called erlotinib, which inhibits a protein called EGFR that is thought to be a key factor in the development and progression of some cancers.
Participants with Kirsten rat sarcoma virus (KRAS), proto-oncogene B-Raf (BRAF), Harvey Rat sarcoma virus (HRAS), or NRAF gene mutations will receive a drug called AZD6244, which inhibits a protein called methyl ethyl ketone (MEK) that is thought to be a key factor in the development and progression of some cancers.
Participants with phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), protein kinase B (AKT), or phosphatase and tensin homolog (PTEN) gene mutations will receive a drug called MK-2206, which inhibits a protein called AKT that is thought to be a key factor in the development and progression of some cancers.
Participants with KIT or platelet-derived growth factor receptor A, (PDGFRA) gene mutations will receive a drug called sunitinib, which inhibits some proteins that are thought to be key factors in the development and progression of some cancers, including kidney cancer.
Participants who have -erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene mutation or amplification will receive a drug called lapatinib, which inhibits some proteins that are thought to be key factors in the development and progression of some cancers, including breast cancer.
Participants who do not have any of the genetic abnormalities described above will be offered different options for treatment, including standard of care chemotherapy or treatment with investigational agents in a different research protocol.
After 6 weeks of treatment, participants will have imaging studies to evaluate the status of their cancer. Treatment will continue as long as participants tolerate the drugs, and the disease does not progress.
Participants who benefit from the first treatment but eventually develop resistance and progression of their cancer will be offered the chance to have a second tumor biopsy and undergo a different treatment for their cancer.

Detailed description

BACKGROUND:

A better understanding of the genetic make-up of the individual tumor may offer potentially improved therapies. This approach may also give rapid access to response data in patients with sometimes rare genetic abnormalities.
In addition, it will allow us to test targeted therapies in a select population of patients that is more likely to have a favorable response based on their molecular profile and the specific mechanism of action of the drug being tested.
This approach will also speed up drug development and potentially approval and rescue an otherwise ineffective drug candidate for the specific subgroup that can benefit.

Primary Objectives:

To determine the feasibility of the use of tumors molecular profiling and targeted therapies in the treatment of advanced stage non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and thymic malignancies.
To estimate the response rate of molecular profile directed treatments in NSCLC, SCLC and thymic malignancies patients.

ELIGIBILITY:

Patients with histologically confirmed advanced lung cancer or thymic malignancies for whom surgical resection with curative intent is not feasible.
Patients must either have biopsiable disease and be willing to undergo biopsy for molecular profiling or have paraffin embedded tissue blocks suitable for molecular profiling analysis.
Individuals are eligible for epidermal growth factor receptor (EGFR) germline mutation testing if they have:
a personal history of invasive lung cancer or one of the pre-invasive histologies associated with the development of lung cancer and more than two affected family members with invasive lung cancer or one of the pre-invasive histologies associated with the development of lung cancer,

a first-degree relative with a known EGFR germline mutation (EGFR exon 20 T790M, exon 21 V843I, exon 21 R831C and exon 20 R776G).

DESIGN:

All patients will have their tumors undergo molecular profiling. Based on these results and on other eligibility criteria, the patients will be offered enrollment into different targeted therapy arms.
At the NCI site only, individuals eligible for EGFR germline mutation will undergo testing for germline mutations affecting the EGFR gene; if a mutation is detected, their first-degree relatives would be invited to undergo testing for the index germline mutation found in the proband and appropriate follow-up on trial.
Effective with Amendment I, the participating site, Oregon Health and Science University (OHSU), will discontinue new enrollments and data entry for existing patients on the Not Other Specified (NOS) arm on this protocol in favor of the OHSU protocol L8639, Personalized Cancer Medicine Registry. The data from these patients will be included with the data from 11-C-0096 (8639) National Cancer Institute (NCI) patients at the time of publication. Any OHSU patients who are eligible for a treatment arm will continue to be enrolled and followed per protocol.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 6

Arm	Type	Receives
A/ Erlotinib	Active comparator	Drug: Erlotinib, Procedure: Molecular ProfilingArm A - Erlotinib 150 mg by mouth (PO) every morning (QAM)
B/ AZD6244	Active comparator	Drug: AZD6244, Procedure: Molecular ProfilingAZD6244 Hydrogen Sulfate 75 mg by mouth (PO) every (Q) 12 Hours
C/ MK-2206	Active comparator	Drug: MK-2206, Procedure: Molecular ProfilingMK-2206 200 mg by mouth (PO) every (Q) Week
D/ Lapatinib	Active comparator	Drug: Lapatinib, Procedure: Molecular ProfilingLapatinib 1500 mg by mouth (PO) every day (QD)
E/Sunitinib	Active comparator	Drug: Sunitinib, Procedure: Molecular ProfilingSunitinib 50 mg by mouth (PO) on days 1-28
F/ Not Otherwise Specified (NOS)	Other	Procedure: Molecular ProfilingParticipants who do not meet the eligibility criteria for enrollment

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (0 listed)

Key exclusion criteria (16 listed)

Patients who have had major surgery, chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.
Patients may not be receiving any other investigational agents or other medications for the treatment of their malignancy.
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. However, patients who have had treatment for their brain metastases and whose brain metastatic disease status has remained stable for at least 1 week after the end of brain radiation may be enrolled to undergo molecular profiling at the discretion of the principal investigator. In addition, brain metastatic disease should be stable for at least 4 weeks, before the patients can be enrolled in any of the experimental treatment arms.
Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain tablets are excluded.
Any uncontrolled medical illness that precludes the patient from undergoing a biopsy for molecular profiling and/or receiving treatment under one of the experimental arms of the study should be excluded. These conditions include but are not limited to:

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
AZD6244Also: SelumetinibCycle = 21 days AZD6244 Hydrogen Sulfate 75 mg by mouth (PO) every (Q) 12 Hours	Drug	B/ AZD6244
MK-2206Cycle = 28 days MK-2206 200 mg by mouth (PO) every (Q) Week	Drug	C/ MK-2206
LapatinibAlso: TykerbCycle = 21 days Lapatinib 1500 mg by mouth (PO) every day (QD)	Drug	D/ Lapatinib
ErlotinibAlso: TarcevaCycle = 21 days Erlotinib 150 mg by mouth (PO) every morning (QAM)	Drug	A/ Erlotinib
SunitinibAlso: SutentCycle = 42 days Sunitinib 50 mg by mouth (PO) on days 1-28	Drug	E/Sunitinib
Molecular ProfilingMolecular profiling of tumor tissue. Not Otherwise Specified (NOS) arm. Participants who do not meet the eligibility criteria for enrollment or who meet eligibility criteria for a particular arm but can't be enrolled	Procedure or surgery	A/ Erlotinib, B/ AZD6244, C/ MK-2206, D/ Lapatinib, E/Sunitinib, F/ Not Otherwise Specified (NOS)

Primary outcome

Percentage of Enrolled Participants Testing Positive for Genomic Abnormality
Time frame: 1 year and 11 months
To determine the feasibility of the use of tumor molecular profiling and targeted therapies in the treatment of Non-Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), and Thymic Malignancies, the trial will be evaluated by determining the percentage of enrolled participants with a genomic abnormality. Identifying molecular profiles may help identify new targeted treatments for cancer.
Number of Evaluable Participants With a Response Based on Molecular Profile Directed Treatments in Non-Small Cell Lung Cancer, (NSCLC), Small Cell Lung Cancer (SCLC), and Thymic Malignancies
Time frame: 1 year and 13 months
Efficacy will be determined by assessing if participants who have treatment assigned on the basis of their molecular profiling results will exhibit reasonable response to the drug selected for their particular profile. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study Progressive Disease (PD) is At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.
Percentage of Evaluable Participants Overall Response Rate (ORR) Based on the Drug Selected for Their Particular Profile
Time frame: 1 year and 13 months
Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).Partial Response (PD) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study Progressive Disease (PD) is At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.

Results and safety

Results posted to the registry on 11 Apr 2023, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Participants With Non-Small Cell Lung Cancer	481	288
Participants With Small Cell Lung Cancer	68	57
Participants With Thymic Malignancies	98	90

Primary outcome: Percentage of Enrolled Participants Testing Positive for Genomic Abnormality

Time frame: 1 year and 11 months. Number. Unit: percentage of participants

Measure	Non-Small Cell Lung Cancer (NSCLC) n = 481	Small Cell Lung Cancer (SCLC) n = 68	Thymic Malignancies n = 98
Tumor protein p53 (TP53)	28.5	44.2	0
Kirsten rat sarcoma virus (KRAS)	24.9	4.1	0
Epidermal growth factor receptor (EGFR)	22.1	2.0	1
PDGFRA amplifications	12.8	–	0
phosphoinositide 3-kinase (PIK3)CA amplifications	11.1	–	–
Anaplastic lymphoma kinase (ALK) trans	8.7	–	0
Discoidin Domain Receptor 2 (DDR2)	6.7	–	–
Phosphatidylinositol 3-kinase (PIK3R2)	6.7	–	–

Population analysed: For tolerability, data has been separated by type of malignancy since the information being conveyed represents overall tolerability in participants with a given malignancy.

Primary outcome: Number of Evaluable Participants With a Response Based on Molecular Profile Directed Treatments in Non-Small Cell Lung Cancer, (NSCLC), Small Cell Lung Cancer (SCLC), and Thymic Malignancies

Time frame: 1 year and 13 months. Count of participants. Unit: Participants

Measure	Non-Small Cell Lung Cancer (NSCLC) n = 36	Small Cell Lung Cancer (SCLC) n = 4	Thymic Malignancies n = 3
Partial Response with Erlotinib	9	–	0
Stable Disease with Erlotinib	5	–	0
Progressive Disease with Erlotinib	1	–	1
Partial Response to Lapatinib	0	0	0
Stable Disease with Lapatinib	4	1	–
Progressive Disease with Lapatinib	2	0	–
Partial Response with Sunitinib	0	–	0
Stable Disease with Sunitinib	1	–	1

Population analysed: Overall number of participants analyzed represent the total number of participants for each tumor type evaluable for response (efficacy) across different treatment arms. For tolerability, data has been separated by type of malignancy since the information being conveyed represents overall tolerability in participants with a given malignancy.

Primary outcome: Percentage of Evaluable Participants Overall Response Rate (ORR) Based on the Drug Selected for Their Particular Profile

Time frame: 1 year and 13 months. Number (95% Confidence Interval). Unit: percentage of participants

Measure	Non-Small Cell Lung Cancer (NSCLC) n = 36	Small Cell Lung Cancer (SCLC) n = 4	Thymic Malignancies n = 3
Overall response rate to Erlotinib	60 (32.3 to 83.7)	–	0 (0 to 0)
Overall response rate to Lapatinib	0 (0 to 0)	0 (0 to 0)	–
Overall response rate to Sunitinib	0 (0 to 0)	–	0 (0 to 0)
Overall response rate to Selumetinib	11 (0 to 48)	0 (0 to 0)	–
Overall response rate to MK2206	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)

Adverse events

Time frame: Date treatment consent signed to date off study, approximately 122 months and 25 days, 88 months and 16 days, and 126 months and 2 days for each group respectively.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Non-Small Cell Lung Cancer (NSCLC)	15 of 310 (4.8%)	37 of 310 (11.9%)	467 of 481
Small Cell Lung Cancer (SCLC)	0 of 22 (0%)	1 of 22 (4.5%)	68 of 68
Thymic Malignancies	3 of 91 (3.3%)	3 of 91 (3.3%)	88 of 98

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 1 Oct 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 18390968Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, Hanson LJ, Gore L, Chow L, Leong S, Maloney L, Gordon G, Simmons H, Marlow A, Litwiler K, Brown S, Poch G, Kane K, Haney J, Eckhardt SG. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008 May 1;26(13):2139-46. doi: 10.1200/JCO.2007.14.4956. Epub 2008 Apr 7.
Background: PubMed 14613031Allen LF, Sebolt-Leopold J, Meyer MB. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol. 2003 Oct;30(5 Suppl 16):105-16. doi: 10.1053/j.seminoncol.2003.08.012.
Background: PubMed 16288292Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005 Nov 14;24(50):7455-64. doi: 10.1038/sj.onc.1209085.
Derived from this study: PubMed 26028668Thomas A, Chen Y, Steinberg SM, Luo J, Pack S, Raffeld M, Abdullaev Z, Alewine C, Rajan A, Giaccone G, Pastan I, Miettinen M, Hassan R. High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis. Oncotarget. 2015 May 10;6(13):11694-703. doi: 10.18632/oncotarget.3429.
Derived from this study: PubMed 25667274Lopez-Chavez A, Thomas A, Rajan A, Raffeld M, Morrow B, Kelly R, Carter CA, Guha U, Killian K, Lau CC, Abdullaev Z, Xi L, Pack S, Meltzer PS, Corless CL, Sandler A, Beadling C, Warrick A, Liewehr DJ, Steinberg SM, Berman A, Doyle A, Szabo E, Wang Y, Giaccone G. Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol. 2015 Mar 20;33(9):1000-7. doi: 10.1200/JCO.2014.58.2007. Epub 2015 Feb 9.
NIH Clinical Center Detailed Web PageLink provided by the sponsor.
Individual participant dataSharing planned: Yes. All Individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Related trials for Carcinoma, Non-Small-Cell Lung

Active, not recruitingPhase 3
A Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Characterized by Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions
Carcinoma, Non-Small-Cell Lung
RecruitingPhase 1
A Study to Find a Suitable Dose of ASP5834 in Adults With Solid Tumors
Solid Tumor, Non-Small-Cell Lung Cancer
RecruitingPhase 1/2
KEYMAKER-U01 Substudy 01A: Efficacy and Safety Study of Pembrolizumab (MK-3475) With or Without Chemotherapy When Used With Investigational Agents in Treatment-naïve Participants With Stage IV Non-small Cell Lung Cancer (NSCLC) (MK-3475-01A/KEYMAKER-U01A)
Carcinoma, Non-Small-Cell Lung
RecruitingPhase 3
A Global Phase III Study of Rilvegostomig or Pembrolizumab Plus Chemotherapy for First-Line Treatment of Locally Advanced or Metastatic Squamous Non-small Cell Lung Cancer (NSCLC)
Non-small Cell Lung Cancer
Active, not recruitingPhase 3
A Study of DZD9008 Versus Platinum-Based Doublet Chemotherapy in Local Advanced or Metastatic Non-small Cell Lung Cancer (WU-KONG28)
Non-small Cell Lung Cancer

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Arun Rajan, M.D. principal investigator

National Cancer Institute (NCI)

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing AZD6244, MK-2206 and Lapatinib in people with Carcinoma, Non-Small-Cell Lung and Carcinoma, Small Cell Lung, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 0 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Apr 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Enrolled Participants Testing Positive for Genomic Abnormality (time frame: 1 year and 11 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01306045, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Oct 2024.