Gene Expression Levels in Predicting Treatment Response in Patients With Stage IV Non-small Cell Lung Cancer

• Sponsor: Barbara Ann Karmanos Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02145078
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 4
• Location: 1
• Arm: 1
• Duration (Months): 33.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This pilot clinical trial studies whether the levels of certain genes in the tissue and blood are related to how well patients with stage IV non-small cell lung cancer respond to chemotherapy. Genes may affect how sensitive or resistant tumors are to chemotherapy. Studying the levels of genes related to tumor response before and after chemotherapy may help doctors learn whether they can predict how well patients will respond to treatment.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer	Drug: docetaxel; Drug: pemetrexed disodium; Drug: gemcitabine hydrochloride; Other: laboratory biomarker analysis	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. To describe the association between baseline gene expression levels at the protein and messenger ribonucleic acid (mRNA) level and best treatment response after two cycles of single-agent or multi-agent chemotherapy

SECONDARY OBJECTIVES:

1. To describe changes in protein and mRNA levels of ribonucleotide reductase M1 (RRM1), thymidylate synthetase (TS), and excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1) in serial biopsies obtained from patients being treated with gemcitabine (gemcitabine hydrochloride), pemetrexed (pemetrexed disodium), and platinum.

2. To describe the association between changes in marker levels and changes in tumor diameters.

TERTIARY OBJECTIVES:

1. To explore the relationship between marker levels in circulating tumor cells and solid tumor specimens.

2. To explore the relationship between marker levels in viable peripheral blood mononuclear cells (PBMCs), circulating tumor cells, and tumor specimens.

3. Should sufficient amounts and numbers of tumor specimens remain after these analyses, they will be used to assess if other genes implicated in non-small cell lung cancer (NSCLC) outcome and response to treatment might be useful as prognostic or predictive markers for patient outcome.

OUTLINE:

Patients receive 1 of 3 chemotherapy regimens at the discretion of the primary oncologist, including docetaxel intravenously (IV) on day 1, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After course 2, patients may continue treatment off-study at the discretion of the treating physician.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Trial of Platinum, Gemcitabine, or Pemetrexed Single- or Multi-Agent Therapy With Serial Tumor Specimen Collection in Patients With Advanced Non-Small-Cell Lung Cancer
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: Jun 18, 2015
• Actual Study Completion Date: Mar 7, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy regimen) Patients receive 1 of 4 chemotherapy regimens at the discretion of the primary oncologist following institutional guidelines, including cisplatin, carboplatin, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After course 2, patients may continue treatment off-study at the discretion of the treating physician.

Drug: docetaxel; Given IV; Other Names: RP 56976 Taxotere TXT ; Drug: pemetrexed disodium; Given IV; Other Names: ALIMTA LY231514 MTA ; Drug: gemcitabine hydrochloride; Given IV; Other Names: dFdC difluorodeoxycytidine hydrochloride gemcitabine Gemzar ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Baseline Marker Measurement [Baseline]

   A univariable regression of continuous disease response on baseline marker value will be performed. A multivariable regression model adjusted for clinical covariates will be evaluated as well. Expression levels of RRM1, TS, BRCA1, and other molecules and disease response after course 2 will be log-transformed.

Secondary Outcome Measures

1. Change in Biomarker Expression Levels [Baseline to up to 8 weeks (after course 2)]

   Evaluated using Pearson correlation. If data are not normally distributed after log transformation, a non-parametric method (e.g., Spearman correlation) will be used.

2. Overall Survival (OS) [From the date of protocol-specified treatment initiation to the date of death or last observation, assessed up to 12 months]

   Since, the study was canceled due to slow accrual, no biomarkers were measured; therefore, no analysis with biomarkers. Only the OS will be calculated.

3. Progression-free Survival (PFS) [From the date of protocol-specified treatment initiation to the date of progression, death, or last observation, assessed up to 12 months]

   Each biomarker evaluated using its expression level (continuous variable) and dichotomous form (based on a median cutoff). A univariable Cox regression model will be used to assess the relationship of expression levels of each biomarker to PFS. In addition, for the dichotomous variables, the sample will be divided into those above and below the median for each biomarker. PFS probabilities for each group will be estimated using the Kaplan-Meier method, with standard errors based on Greenwood's formula. Log rank tests will be used to determine the level of significance between survival curves. Since, the study was canceled due to slow accrual, no biomarkers were measured; therefore, no analysis with biomarkers. Only the PFS will be calculated.

4. Expression Levels of Biomarkers and Other Molecules [Up to 8 weeks (end of course 2)]

   To assess the relationship between expression levels of RRM1, TS, BRCA1, and other molecules and demographic and disease variables, the Wilcoxon rank sum test or Kruskal-Wallis test for dichotomous or polychotomous categorical variables (such as sex, and histology) and the Spearman correlation coefficient for continuous ordinal variables (such as age or stage) will be used.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with advanced stage NSCLC who are candidates for single or multi-agent first-line therapy.

• Second-line or higher therapy for any patients with NSCLC with performance status (PS) 0-2

• Maintenance therapy for patients after completion of four cycles of dual-agent platinum-based chemotherapy

• Stage IV, histologically or cytologically confirmed NSCLC; confirmation may be obtained with the first protocol-specified tumor biopsy

• White blood cell count > 3000/mm^3

• Platelet count > 100,000/mm^3

• Hemoglobin > 9.0 g/dl

• A tumor lesion that can be safely biopsied as judged by the treating oncologist and physician performing the procedure and has not been radiated

• At least one unidimensionally measurable tumor lesion >= 1 cm in longest diameter using spiral CT (>= 2 cm in longest diameter by any other technique) that has not been radiated and is not located in a bone

• Performance status 0-2 by Eastern Cooperative Oncology Group criteria

• Life expectancy of >= 3 months

• Able to understand and sign the informed consent document

Exclusion Criteria:

• Therapy that does not include cisplatin, carboplatin, gemcitabine, and/or pemetrexed

• Concomitant medical or psychiatric illness that is likely to interfere with a reasonably safe execution of the treatment plan

• Concomitant malignancy other than NSCLC that requires active therapy; prior malignancies are allowed as long as the disease is controlled and does not require ongoing therapy of any kind; prior therapy must have concluded at least 1 year before treatment initiation on this protocol; exceptions are non-melanoma skin cancer, prostate cancer and prostatic intraepithelial neoplasia (PIN) treated with local intervention and deemed cured, cervical cancer and carcinoma in situ (CIS) treated with local intervention and deemed cured, and laryngeal cancer and CIS treated with local intervention and deemed cured

• Carcinomatous meningitis

• Uncontrolled central nervous system (CNS) disease

• The time interval between CNS radiation, whole brain radiation, spinal cord radiation, or radiosurgery, and initiation of protocol specified chemotherapy must be at least 1 week

• Malignant pleural, pericardial, or peritoneal effusion if it is the only site of disease activity; i.e., if no other measurable tumor lesions exist

• Coagulopathy or anticoagulation therapy that cannot be safely corrected or interrupted for tumor biopsy

• Significant hepatic dysfunction, renal dysfunction, or metabolic derangement that precludes full-dose chemotherapy at the specified starting doses

• Concomitant treatment with chemotherapeutic agents for diseases other than malignancy

• Pregnancy or lactation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201

Sponsors and Collaborators

• Barbara Ann Karmanos Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Gerold Bepler, Barbara Ann Karmanos Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 30, 2015

More Information

Publications

None provided.

• Responsible Party: Gerold Bepler, Principal Investigator, Barbara Ann Karmanos Cancer Institute
• ClinicalTrials.gov Identifier: NCT02145078
• Other Study ID Numbers: 2013-177; NCI-2014-01023; 1402012854; 2013-177; P30CA022453
• First Posted: May 22, 2014
• Last Update Posted: Sep 24, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Gemcitabine; Docetaxel; Pemetrexed

Study Results

Participant Flow

Arm/Group Title	Treatment (Chemotherapy Regimen)
Arm/Group Description	Patients receive 1 of 4 chemotherapy regimens at the discretion of the primary oncologist following institutional guidelines, including cisplatin, carboplatin, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After course 2, patients may continue treatment off-study at the discretion of the treating physician. docetaxel: Given IV pemetrexed disodium: Given IV gemcitabine hydrochloride: Given IV laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	4
COMPLETED	0
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Treatment (Chemotherapy Regimen)
Arm/Group Description	Patients receive 1 of 4 chemotherapy regimens at the discretion of the primary oncologist following institutional guidelines, including cisplatin, carboplatin, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After course 2, patients may continue treatment off-study at the discretion of the treating physician. docetaxel: Given IV pemetrexed disodium: Given IV gemcitabine hydrochloride: Given IV laboratory biomarker analysis: Correlative studies
Overall Participants	4
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 75%
>=65 years	1 25%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	4 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%

Outcome Measures

1. Primary Outcome

Title	Baseline Marker Measurement
Description	A univariable regression of continuous disease response on baseline marker value will be performed. A multivariable regression model adjusted for clinical covariates will be evaluated as well. Expression levels of RRM1, TS, BRCA1, and other molecules and disease response after course 2 will be log-transformed.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

No patient was analyzed.

Arm/Group Title	Treatment (Chemotherapy Regimen)
Arm/Group Description	Patients receive 1 of 4 chemotherapy regimens at the discretion of the primary oncologist following institutional guidelines, including cisplatin, carboplatin, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After course 2, patients may continue treatment off-study at the discretion of the treating physician. docetaxel: Given IV pemetrexed disodium: Given IV gemcitabine hydrochloride: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

2. Secondary Outcome

Title	Change in Biomarker Expression Levels
Description	Evaluated using Pearson correlation. If data are not normally distributed after log transformation, a non-parametric method (e.g., Spearman correlation) will be used.
Time Frame	Baseline to up to 8 weeks (after course 2)

Outcome Measure Data

Analysis Population Description

No patient was analyzed.

Arm/Group Title	Treatment (Chemotherapy Regimen)
Arm/Group Description	Patients receive 1 of 4 chemotherapy regimens at the discretion of the primary oncologist following institutional guidelines, including cisplatin, carboplatin, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After course 2, patients may continue treatment off-study at the discretion of the treating physician. docetaxel: Given IV pemetrexed disodium: Given IV gemcitabine hydrochloride: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Since, the study was canceled due to slow accrual, no biomarkers were measured; therefore, no analysis with biomarkers. Only the OS will be calculated.
Time Frame	From the date of protocol-specified treatment initiation to the date of death or last observation, assessed up to 12 months

Outcome Measure Data

Analysis Population Description

All eligible patients.Since, the study was canceled due to slow accrual, no biomarkers were measured; therefore, no analysis with biomarkers. Only the OS will be calculated.

Arm/Group Title	Treatment (Chemotherapy Regimen)
Arm/Group Description	Patients receive 1 of 4 chemotherapy regimens at the discretion of the primary oncologist following institutional guidelines, including cisplatin, carboplatin, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After course 2, patients may continue treatment off-study at the discretion of the treating physician. docetaxel: Given IV pemetrexed disodium: Given IV gemcitabine hydrochloride: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	4
Median (Full Range) [months]	2.0

4. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Each biomarker evaluated using its expression level (continuous variable) and dichotomous form (based on a median cutoff). A univariable Cox regression model will be used to assess the relationship of expression levels of each biomarker to PFS. In addition, for the dichotomous variables, the sample will be divided into those above and below the median for each biomarker. PFS probabilities for each group will be estimated using the Kaplan-Meier method, with standard errors based on Greenwood's formula. Log rank tests will be used to determine the level of significance between survival curves. Since, the study was canceled due to slow accrual, no biomarkers were measured; therefore, no analysis with biomarkers. Only the PFS will be calculated.
Time Frame	From the date of protocol-specified treatment initiation to the date of progression, death, or last observation, assessed up to 12 months

Outcome Measure Data

Analysis Population Description

No analysis with biomarkers.

Arm/Group Title	Treatment (Chemotherapy Regimen)
Arm/Group Description	Patients receive 1 of 4 chemotherapy regimens at the discretion of the primary oncologist following institutional guidelines, including cisplatin, carboplatin, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After course 2, patients may continue treatment off-study at the discretion of the treating physician. docetaxel: Given IV pemetrexed disodium: Given IV gemcitabine hydrochloride: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	4
Median (Full Range) [days]	42

5. Secondary Outcome

Title	Expression Levels of Biomarkers and Other Molecules
Description	To assess the relationship between expression levels of RRM1, TS, BRCA1, and other molecules and demographic and disease variables, the Wilcoxon rank sum test or Kruskal-Wallis test for dichotomous or polychotomous categorical variables (such as sex, and histology) and the Spearman correlation coefficient for continuous ordinal variables (such as age or stage) will be used.
Time Frame	Up to 8 weeks (end of course 2)

Outcome Measure Data

Analysis Population Description

No patient was analyzed.

Arm/Group Title	Treatment (Chemotherapy Regimen)
Arm/Group Description	Patients receive 1 of 4 chemotherapy regimens at the discretion of the primary oncologist following institutional guidelines, including cisplatin, carboplatin, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After course 2, patients may continue treatment off-study at the discretion of the treating physician. docetaxel: Given IV pemetrexed disodium: Given IV gemcitabine hydrochloride: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0

Adverse Events

Time Frame	Through study completion, an average of 3 months
Adverse Event Reporting Description	Only biopsy related AEs and SAEs were to be reported.
Arm/Group Title	Treatment (Chemotherapy Regimen)
Arm/Group Description	Patients receive 1 of 4 chemotherapy regimens at the discretion of the primary oncologist following institutional guidelines, including cisplatin, carboplatin, pemetrexed disodium IV on day 1, or gemcitabine hydrochloride IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. After course 2, patients may continue treatment off-study at the discretion of the treating physician. docetaxel: Given IV pemetrexed disodium: Given IV gemcitabine hydrochloride: Given IV laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (Chemotherapy Regimen)
	Affected / at Risk (%)	# Events
Total	4/4 (100%)
Serious Adverse Events
	Treatment (Chemotherapy Regimen)
	Affected / at Risk (%)	# Events
Total	0/4 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Chemotherapy Regimen)
	Affected / at Risk (%)	# Events
Total	0/4 (0%)

Limitations/Caveats

This study was stopped because of low accrual.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.