Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Immune System Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Hypersensitivity

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Vitamins

Vinorelbine

Pemetrexed

Cisplatin

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Tubulin Modulators

Antimitotic Agents

Folinic Acid

Folate

Vitamin B9

Resected tumor was used for genomic expression profiling. Patients with a genomic expression pattern suggestive of vinorelbine sensitivity were given cisplatin + vinorelbine.

Resected tumor was used for genomic expression profiling. Patients with a genomic expression pattern suggestive of pemetrexed sensitivity were given cisplatin + pemetrexed.

Vinorelbine 25 mg/m2 IV over 6-10 minutes on days 1 and 8, followed by Cisplatin 75 mg/m2 IV over 60 minutes on day 1 (every 21 days x 4 cycles).

Vinorelbine followed by Cisplatin

Pemetrexed 500 mg/m2 IV infusion over approximately 10 minutes on day 1, followed by Cisplatin 75 mg/m2 IV over 60 min on day 1 (every 21 days x 4 cycles)

Pemetrexed followed by Cisplatin

Neal Ready, Ph.D., M.D.

This study assigned subjects to either cisplatin/vinorelbine or cisplatin/pemetrexed chemotherapy using a genomic based expression profile to determine chemotherapy sensitivity in completely resected early stage non-squamous non-small-cell lung cancer (NSCLC). The vinorelbine-sensitive tumors group received Vinorelbine followed by cisplatin, while the pemetrexed-sensitive tumors group received pemetrexed followed by cisplatin. The primary objective of this trial was to determine whether genomic-based adjuvant chemotherapy treatment increased the 2-year progression-free survival rate in completely resected patients with NSCLC compared to historic controls. Secondary objectives included: 1) estimation of the percentage of completely resected NSCLC tumors that can be adequately analyzed and used to direct specific adjuvant chemotherapy; 2) estimation of the proportion of patients who are assigned to treatment with vinorelbine and pemetrexed; 3) evaluation of drug sensitivity patterns of cisplatin and pemetrexed in both treatment arms; 4) description of the overall median survival experience of treated patients; and 5) assessment of patient understanding and perceptions of participating in a clinical trial evaluating cancer genomics for adjuvant treatment of early stage lung cancer.

The proposed study is a multi-center open label phase II study of the chemotherapy doublets cisplatin/vinorelbine and cisplatin/pemetrexed as adjuvant therapy in early stage non-squamous NSCLC.

Eligible patients had no previous treatment for the current diagnosis of NSCLC. The two treatment groups of patients will be determined by gene expression profile analysis of each patient's tumor: one group of vinorelbine-sensitive patients and one group of pemetrexed-sensitive patients. The genomic expression profiling that was utilized generated a percentage for likelihood of chemotherapy sensitivity. Patients were directed to receive the chemotherapy regimen for which the percentage of predicted sensitivity is highest. For instance, if the model predicted the likelihood of tumor sensitivity was 46% to vinorelbine and 48% to pemetrexed, then the adjuvant chemotherapy would be directed to cisplatin/pemetrexed. Patients whose tumors could not be adequately analyzed for gene expression were offered adjuvant therapy off protocol as deemed appropriate by their primary oncologist. Patients with either squamous or non-squamous cell histology were eligible to participate in this study as indicated in study protocols dated prior to January 25, 2010. An amendment to the protocol on January 25, 2010 indicated inclusion of only non-squamous histology. However, because of low accrual after January 25, 2010 (5 patients, including 2 screen failures), this report reflects the original study outcomes that includes both squamous and non-squamous histologies.

Thirty-one patients with stage IB (\> 4 cm), II or IIIA non-squamous NSCLC were enrolled, from which 24 were assigned treatment. The vinorelbine-sensitive tumors group received Vinorelbine 25 mg/m2 days 1 and 8, followed by cisplatin 75 mg/m2 day 1, every 21 days for 4 cycles. The pemetrexed-sensitive tumors group received pemetrexed 500 mg/m2 day 1 followed by cisplatin 75 mg/m2 day 1, every 21 days for 4 cycles. Standard pre-medication regimens included dexamethasone, vitamin B12 and folate supplementation in the pemetrexed group. Patients in both groups will receive up to a maximum of 4 cycles of therapy.

Subsequent reevaluation of the genomic signatures of chemotherapy sensitivity have shown that they were irreproducible, suggesting inaccurate patient assignments into the two treatment arms. As a result, it would be inappropriate to separately analyze outcomes for the different treatment groups. Instead, information from both arms will be combined to reflect the overall measure of two-year progression-free survival in this study. Similarly for secondary objectives, both arms will be combined to address endpoints.

To assess patient understanding and perceptions of participating in a clinical trial evaluating cancer genomics for adjuvant treatment of early stage lung cancer, patients provided responses for the following questions at baseline:

1. Did your doctor talk to you today about choosing chemotherapy treatment for lung cancer based on the genomics of your tumor?
2. How well did you understand what you doctor told you about choosing chemotherapy based on the genomics of your tumor? (circle a number between 1 and 7, where 1 = very poorly and 7 = very well)
3. Do you think the type of chemotherapy that you will get is based on the genomics of your tumor?
4. Do you think you will get better medical care for the treatment of your lung cancer if it is based on the genomics of your tumor?
5. To what extent do you think treating lung cancer based on the genomics of the tumor will lead to more successful treatment strategies? (circle a number between 1 and 7, where 1 = definitely will not lead to a more successful treatment and 7 = definitely will lead to a more successful treatment)
6. How effective do you think chemotherapy will be at stopping your cancer from coming back? (circle a number between 1 and 7, where 1 = not at all effective and 7 = completely effective)
7. To what extent is YOUR lung cancer primarily caused by genetics? (circle a number between 1 and 7, where 1 = not at all caused by genetics and 7 = completely caused by genetics)
8. To what extent to do you think your lung cancer is treatable? (circle a number between 1 and 7, where 1 = definitely not treatable and 7 = definitely treatable)
9. Did your doctor talk to you about your chance of your lung cancer coming back? (Yes - go to question 10, No - go to question 11, Do not know - go to question 11)
10. What did your doctor say was your chance of your cancer coming back? (Low Risk, Moderate or intermediate risk, High risk, Do not know)
11. What do you think is your chance of your lung cancer coming back in the next year on a scale from 1 to 7 where 1=definitely will not come back and 7=definitely will come back?
12. How worried are you that your lung cancer will come back in the next year? (circle a number between 1 and 7, where 1=not at all worried and 7=extremely worried)

Adjuvant Cisplatin With Either Genomic-Guided Vinorelbine or Pemetrexed for Early Stage Non-Small-Cell Lung Cancer

Phase II Prospective Study Evaluating the Role of Directed Cisplatin Based Chemo With Either Vinorelbine or Pemetrexed for the Adj Tx of Early Stage NSCLC in Patients Using Genomic Expression Profiles of Chemo Sensitivity to Guide Therapy

Progression-free survival time was defined as the time from initiation of study treatment to the first date of disease progression or death as a result of any cause. Progression was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Time was censored at the date of the last follow-up visit for patients who were still alive and have not progressed. The two-year progression free survival rate is a percentage, representing the fraction of treated patients who, after two years, are disease free or alive.

The percentage of patients with completely resected NSCLC tumors who had successful genomic analysis and assigned to treatment among patients. All 31 patients enrolled in the study had completely resected tumors. These tumors included a mixture of squamous and non-squamous histologies as indicated the original protocol. However, an amendment dated January 25, 2010 limited eligibility to patients with non-squamous disease. Given that only 5 patients were accrued into the study after this amendment, results reported will consider all histologies.

Overall survival time was defined as the time from initiation of study treatment to the date of death as a result of any cause. Time was censored at the date of the last follow-up visit for patients who were still alive. The two-year overall survival rate is a percentage, representing the fraction of treated patients who, after two years, are alive

Do to space limitations, see the Detailed Description in the study protocol for the wording of the questions used in the Patient Expectations Questionnaire.

Using genomics-based prediction models previously developed separately for cisplatin and pemetrexed, the probability that each patient was sensitive or would respond to treatment was computed. Quartiles describe the patterns of drug sensitivity probabilities. The 1st, 2nd, and 3rd quartiles are the sensitivity levels at which 25%, 50%, and 75% of patients have lower sensitivity. There is lack of integrity regarding the available data due to irreproducible genomic signatures. Therefore the results of this outcome are not presented.

Eli Lilly and Company

Duke University

No adverse events were observed for patients considered screen failures.

Arm A-Vinorelbine

Arm B-Pemetrexed

Patients who were registered and underwent protocol-based procedure (e.g. biopsy, genomic screening), but were not assigned to or administered genomics-directed, protocol-based therapy.

Note that two patients who were assigned protocol-based treatment (1 in each arm) did not receive the treatment and were added to the 7 initially identified as screen failures within the summary of baseline characteristics and outcome measures.

Screen Failures

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

One patient in each of the vinorelbine and pemetrexed arms did not undergo protocol-based treatment, resulting in 22 total patients who were treated with either vinorelbine or pemetrexed. These two enrolled patients who were not administered treatment were added to the 7 original screen failures.

Neal Ready, PhD, MD

Treatment refers to patients treated in the combined vinorelbine and pemetrexed arms of the study. Due to the irreproducibility of the genomics-based prediction model for assigning patients into the original cisplatin treatment arms, patients from both arms were combined for primary outcome analysis.

Treatment

Due to the irreproducible nature of the genomic signatures of chemotherapeutic sensitivity, analyses based on separate treatment groups were inappropriate. Therefore, all enrolled participants (initiated for treatment) from both treatment arms were analyzed together.

2-Year Progression-Free Survival Rate in Patients With Completely Resected Stage IB, II, or IIIA NSCLC

All registered/enrolled patients are included in this outcome, which was measured at the time of consent.

All Registered Patients

Percentage of Patients With Completely Resected NSCLC Tumors That Can Be Analyzed and Used to Direct Adjuvant Chemotherapy

Treatment refers to patients treated in the combined vinorelbine and pemetrexed arms of the study.

2-Year Overall Survival in Patients Treated for NSCLC

Twenty-six questionnaires were returned. There was insufficient numbers to provide for substantive analysis.

Patient Understanding and Perceptions of Participating in a Clinical Trial Evaluating Cancer Genomics for Adjuvant Treatment of Early Stage Lung Cancer

There is lack of integrity regarding the available data due to irreproducible genomic signatures. Therefore the results of this outcome are not presented.

Compare Drug Sensitivity Patterns of Cisplatin and Pemetrexed in Both Treatment Arms

Overall Study

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Breast Neoplasms

Pathologic Complete Response

Breast Diseases

Skin Diseases

Antirheumatic Agents

Anti-Infective Agents

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Docetaxel

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Genomically-guided treatment allocation.

This arm has the following cohorts:

* AC sensitive patients \[\>60% probability of response to AC\]
* TC sensitive patients \[\>60% probability of response to TC\]
* Patients sensitive to neither AC nor TC; randomized to AC or TC

Non-genomically-guided treatment allocation.

This arm has the following cohorts:

* In patients randomly assigned to AC:

  * Patients sensitive to AC
  * Patients sensitive to TC
  * Patients sensitive to neither AC nor TC
* In patients randomly assigned to TC:

  * Patients sensitive to AC
  * Patients sensitive to TC
  * Patients sensitive to neither AC nor TC

Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) or Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy

Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)

Paul K Marcom, MD

This multi-center randomized Phase II study assigned HER2-negative early-stage breast cancer patients to receive preoperative systemic chemotherapy in either a "genomic-guided" arm or a "non-guided arm." The "genomic-guided" method (Arm 1) used genomic expression profiling to assign the preoperative therapy (Doxorubicin/Cyclophosphamide (AC) versus Docetaxel/Cyclophosphamide (TC), while Arm 2 used random assignment to these two therapies.

Primary Objective 1 was to test for an arm difference in pathological complete response rates. Secondary Objective 2 was to estimate and test the difference in pathologic complete response rates between drug-sensitive patients who received their preferred drug and drug-resistant patients randomized to AC or TC.

Secondary objectives included: to determine the 60% cutoff for the genomic profiles resulted in a larger pathologic CR rate for the guided arm than for the unguided arm; to compare the pathologic CR rates of patients whose genomic predictive probabilities indicated that they were resistant to both chemotherapy regimens with the pathologic CR rates of patients whose genomic predictive probabilities indicated that they were sensitive to only one treatment and who were then randomly assigned to a treatment for which they were resistant (combining AC and TC subgroups); Secondary Objective 3 in patients with T2 and T3 tumors classified as requiring mastectomy at baseline, compare the guided and non-guided treatment arms on rates of breast conserving surgery with negative final margins; Secondary Objective in patients with T2 tumors classified as potential candidates for breast conservation, compare the guided and non-guided arms on rates of breast conserving surgery at first attempt; Secondary Objectives 5, 6, 7 and 8 to correlate genomic profiles (i.e., genomic predictive probabilities) with clinical response, disease-free survival, sites of recurrence, and overall survival; Secondary Objective 9:to compare the mean cost of guided versus non-guided treatment; and Secondary Objective 10 to assess patient perceptions of participating in a clinical trial that evaluated cancer genomics for preoperative systemic therapy of early-stage breast cancer.

Objective 10 details: Due to space limitations in the Outcome Measure Description field, details are supplied here:

To assess patient motivation and participation for study participation in a clinical trial evaluating cancer genomics for treatment patients provided responses for the following questions at both baseline (the day of chemotherapy start) and following post-surgical medical oncology evaluation:

One of the goals of this study is to tailor your cancer treatments for you based upon a genomic analysis of your tumor. How much did the knowledge that the treatment is potentially tailored specifically for your tumor influence your decision to participate in this study? (Select One)

Response 1: I did not know that the treatment was tailored.

Response 2: I do not understand what "tailored treatment based upon genomic analysis of "my tumor" means.

Response 3: The information that this was a tailored treatment based upon genomic analysis of my tumor decreased my willingness to participate in this study.

Response 4: The information that this was a tailored treatment based upon genomic analysis of my tumor was of neutral value in the decision making process to participate in this study and did not influence my decision to participate.

Response 5: The information that this was a tailored treatment based upon genomic analysis of my tumor played a minor role in helping me decide to participate in the study.

Response 6: The information that this was a tailored treatment based upon genomic analysis of my tumor played a major role in helping me decide to participate in the study.

Response 7: The information that this was a tailored treatment based upon genomic analysis of my tumor was the primary reason that I decided to participate in the study.

Trial to Evaluate Genomic Expression Profiles to Direct Preoperative Chemotherapy in Early Stage Breast Cancer

A Randomized Phase II Trial Evaluating the Performance of Genomic Expression Profiles to Direct the Use of Preoperative Chemotherapy for Early Stage Breast Cancer

Pathological complete response (pCR) was defined as the disappearance of all invasive disease in the breast or if only residual in situ or lymph node disease is found. The pCR rate is presented with its 95% confidence interval for the Guided and Non-guided arms.

To determine in early stage breast cancer treated with PST whether genomic profiling can identify drug-sensitive and drug-resistant patients including a comparison of subgroups for the two individual regimens (i.e. AC and TC). To determine if the 60% cutoff for the genomic profiles is optimal in predicting the response to chemotherapy regimens.To describe the performance of the genomic profiles in assessing the relative responsiveness of: 1) Patients predicted to be resistant to both chemotherapy regimens; and 2) Patients randomly assigned to one treatment whose genomic profiles suggest receiving the other regimen (in both AC and TC subgroups).

The percentage of patients who had breast-conserving surgery with negative margins, measured in patients with T2 and T3 tumors classified as requiring mastectomy at baseline.

The percentage of patients who had breast-conserving surgery at first attempt, measured only in patients with T2 tumors classified as potential candidates for breast conservation.

WHO criteria are based on the sum of the products of the longest axis and the longest perpendicular axis. Bi-dimensional measurements were taken of all breast lesions and axillary nodes using the best imaging modality performed after completion of assigned therapy.

Clinical Complete Response (cCR): Disappearance of all target lesions by physical exam and best imaging modality.

Clinical Partial Response (cPR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the sum LD at treatment initiation. Patients having a documented response with no reconfirmation of the response will be listed with stable disease.

Progression (PD): At least a 20% increase in the sum of the LD of target lesions or the appearance of one or more new lesion.

Disease-free survival is defined as the length of time from enrollment to local or distant disease recurrence, whichever comes first; disease-free deaths are censored. The 2-year disease-free survival rate is estimated with its 95% confidence interval.

Sites of Recurrence is a categorical outcome whose possible values are the organ-specific sites at which disease recurrence was observed. A patient may recur at more than one site.

Overall survival is defined as the time from enrollment to death due to any cause. The 2-year overall survival rate is estimated with the Kaplan-Meier method.

Economic Impact (i.e., cost of care) will be calculated by first assessing the quantity of clinical resources used by each patient in the study arm, and then assigning a cost to each resource using cost information derived from a costing study to be undertaken outside of this protocol.

A short questionnaire was administered at baseline (the day chemotherapy was started) and following post-surgical medical oncology evaluation to assess the patient's understanding of the study being conducted, and the patient's expectations of the treatment. Due to space limitations, the full survey is presented in the Detailed Description.

United States Department of Defense

Genomically-guided \>60% probability of response to AC

AC: Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) every 3 weeks for 4 cycles as neoadjuvant therapy

Guided AC Sensitive

Genomically-guided treatment \>60% probability of response to TC

TC: Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy

Guided TC Sensitive

Genomics guided treatment \<60% probability of response to both AC and TC; randomized to AC

AC: Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) every 3 weeks for 4 cycles as neoadjuvant therapy

Guided AC Non-sensitive

Genomics guided treatment \<60% probability of response to both AC and TC; randomized to TC

TC: Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy

Guided TC Non-Sensitive

Non-genomics guided treatment; randomized to AC

AC: Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) every 3 weeks for 4 cycles as neoadjuvant therapy

Non-guided AC

Non-genomics guided treatment; randomized to TC

TC: Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy

Non-guided TC

Screen failures constitute patients who were registered to the study but were not assigned treatment for various reasons.

Screen Failure

All patients who signed a consent form are included in the baseline analysis.

P. Kelly Marcom, M.D.

Guided Arm

Non-genomically-guided treatment allocation.

Non-Guided Arm

All eligible treated patients. The three patients not included are two who had allergic reactions to the assigned treatment, and one with metastatic disease on biopsy of a spine lesion at the end of assigned treatment so never went to surgery.

Pathologic Complete Response (pCR) Rate in Patients With HER2-negative Early-stage Breast Cancer

This outcome is not summarized due to irreproducibility of the genomics-based prediction model and resulting probability estimates

Probabilities of Being Sensitive to AC and TC as Determined by the Patient's Genomic Signatures

Since final margin status was not collected, this analysis could not be done.

Percentage of Patients Who Had Breast-conserving Surgery With Negative Margins

Data from all eligible patients with non-missing values on this outcome were used.

To Percentage of Patients Who Had Breast-conserving Surgery at First Attempt.

Complete Response (cCR)

Partial Response (cPR)

Stable Disease

Progressive Disease

Not Evaluable/Not Assessed

All eligible treated patients were used in this analysis.

Clinical Response Using WHO Criteria

Disease-free Survival

Bone

Brain

Chest Wall

Liver

Lung

All eligible treated patients. Four of these 38 participants experienced recurrence of their breast cancer; two of the four patients had multiple sites of recurrence.

Sites of Recurrence

All eligible treated patients with known follow-up status.

Overall Survival

Since these data were not collected, this analysis could not be done.

Economic Impact of Using Genomic Assessment to Guide Management.

The overall enrollment was insufficient to provide for any substantive analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Adjuvant Cisplatin With Either Genomic-Guided Vinorelbine or Pemetrexed for Early Stage Non-Small-Cell Lung Cancer	NCT00545948	Carcinoma, Non-...	Vinorelbine fol... Pemetrexed foll...	18 Years -	Duke University
Trial to Evaluate Genomic Expression Profiles to Direct Preoperative Chemotherapy in Early Stage Breast Cancer	NCT00636441	Early-Stage Bre...	Doxorubicin/Cyc...	18 Years -	Duke University

Spots Global Cancer Trial Database for genomic expression profiles