Clinical trial NCT01085630
Conditions: Malignant Mesothelioma
Keywords: epithelial mesothelioma sarcomatous mesothelioma stage II malignant mesothelioma stage III malignant mesothelioma stage IV malignant mesothelioma
Sponsor: Alliance for Clinical Trials in Oncology
Start date: 2010-04-01; Completion date: 2021-04-01
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This randomized phase II trial is studying how well pemetrexed disodium or observation works in treating patients with malignant pleural mesothelioma without progressive disease after first-line chemotherapy.

Detailed description:
OBJECTIVES:

Primary

* To determine if maintenance therapy with pemetrexed disodium versus observation improves progression-free survival of patients with malignant pleural mesothelioma who have at least stable disease after completion of first-line therapy comprising pemetrexed disodium with cisplatin or carboplatin.

Secondary

* To determine the overall survival of patients treated with this regimen versus observation.
* To evaluate the frequency of responses in patients treated with this regimen.
* To assess the toxicity of this regimen in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to first-line chemotherapy regimen (cisplatin/pemetrexed disodium vs carboplatin/pemetrexed disodium), histologic subtype (epithelioid vs other) and number of courses received (\< 6 vs 6).

* Arm I: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients undergo observation until disease progression. After completion of study therapy, patients are followed up every 6 months for 3 years.

Arms: arm 1: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients undergo observation until disease progression.
Interventions: intervention 1: pemetrexed disodium intervention 2: clinical observation
Intervention descriptions: intervention 1: Given IV intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
Participating NCTN Groups: ECOG/ACRIN, Alliance for Clinical Trials in Oncology, NRG, SWOG 
 
 
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ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
CALGB 30901 
 
RANDOMIZED PHASE II STUDY OF MAINTENANCE PEMETREXED VERSUS OBSERVATION FOR PATIENTS 
WITH MALIGNANT PLEURAL MESOTHELIOMA WITHOUT PROGRESSION AFTER FIRST-LINE 
CHEMOTHERAPY 
 
Study Chair 
Arkadiusz Z. Dudek M.D., Ph.D. 
University of Illinois Cancer Center 
 
 
 
 
 
 
 
Respiratory Correlative Science Chair 
 
 
 
 
 
Imaging Co-Chair 
Pathology Co-Chair 
 
 
 
 
 
 
Respiratory Committee Chair 
Mesothelioma Subcommittee Chair 
 
 
 
 
 
 
Study Statistician 
 
 
Data Coordinator 
Protocol Coordinator 
 
 
 
 
 
 
 
 
 


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Study Resources: 
 
Expedited Adverse Event Reporting 
http://eapps-ctep.nci.nih.gov/ctepaers/ 
 Medidata Rave iMedidata portal 
https://login.imedidata.com 
OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org 
 Biospecimen Management System 
http://bioms.allianceforclinicaltrialsinoncology.org 
 
Protocol Contacts: 
 
CALGB 30901 Nursing Contact 
 
 
 
 
CALGB 30901 Pharmacy Contact  
 
 
 
Alliance Biorepository at Ohio State 
The Ohio State University 
Innovation Centre 
 
 
 
 
IROC 
The Ohio State University 
Wright Center of Innovation 
 
 
 
 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory 
requirements: 
For patient enrollments:  
For study data submission:  
Regulatory documentation 
must submitted to the CTSU 
via the Regulatory 
Submission Portal: 
 
Regulatory Submission 
Portal (Sign in at 
www.ctsu.org, and select the 
Regulatory Submission sub-
tab under the Regulatory 
tab.)  
Institutions with patients 
waiting that are unable to 
use the Portal should alert 
the CTSU Regulatory Office 
immediately at 
to receive further 
instruction and support. 
 
Contact the CTSU 
Regulatory Help Desk at 
 for regulatory 
assistance. 
 
Please refer to the patient 
enrollment section for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_
SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
 
 
Data collection for this study will be 
done exclusively through Medidata 
Rave.  Please see the data submission 
section of the protocol for further 
instructions. 
 
The study protocol and all related forms and documents must be downloaded from the protocol-
specific page of the CTSU Member website located at https://www.ctsu.org. Access to the CTSU 
members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and 
Access Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM 
username and password. Permission to view and download this protocol and its supporting documents 
is restricted and is based on person and site roster assignment housed in the CTSU RSS.   
 
For clinical questions (i.e., patient eligibility or treatment-related) see the Protocol Contacts, Page 
2. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line –
, or 
. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU website is located at https://www.ctsu.org. 
 
 
 
 
 


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Randomized phase II study of maintenance pemetrexed versus observation for patients with 
malignant pleural mesothelioma without progression after first-line chemotherapy 
 
 
 
Patient Eligibility 
Required Initial Laboratory Values (for  
Registration Criteria 
Randomization Only) 
Histologically documented unresectable  
Granulocytes 
≥ 1,500/ul 
malignant pleural mesothelioma  
Platelet count 
≥ 100,000/ul 
Prior Treatment : Prior intracavitary cytotoxic or 
sclerosing therapy, prior surgery and prior 
radiotherapy are allowed 
Total Bilirubin 
AST (SGOT) 
Creat. clearance by 
≤ 1.5 x ULN 
≤ 2 x ULN 
≥ 45 ml/min 
Age ≥ 18 years  
Cockcroft/Gault 
 
Non-pregnant and non-nursing 
 
 
Randomization Criteria 
 
 
CR, PR or SD after 4, 5 or 6 cycles of pemetrexed 
+ cisplatin or carboplatin 
 
 
≤ 6 cycles of pemetrexed + cis or carbo 
 
 
ECOG Performance Status 0-1 
 
 
 
SCHEMA 
 
1 cycle = 3 weeks 
 
REGISTER (no later than the last day of cycle 4 of first-line therapy) 
Continue treatment with pemetrexed + platinum  
4, 5, or 6 cycles  
 
            CR, PR, or SD    
 
RANDOMIZE* 
Stratify: 
Cisplatin vs. Carboplatin 
Epithelioid Histology vs. Other 
Number of cycles received: < 6 vs. 6 cycles 
     
     
 
 
 
 
 
  
 
  
Arm A  
 
 
 
 
 
 
Arm B 
Observation 
 
 
 
 
 
Continue pemetrexed 
 
 
 
 
 
until progression or intolerable toxicity 
 
 
* Patients will be randomized following cycle 4, 5 or 6, within 1 week of completing first-line 
treatment. If randomized to pemetrexed, treatment will begin within 14 days of randomization. 
 
 


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TABLE OF CONTENTS 
 
 
SECTION 
PAGE 
_Toc530400544 
1.0     INTRODUCTION ................................................................................................................... 7 
1.1     Chemotherapy for Mesothelioma .......................................................................... 7 
1.2     Duration of Therapy .............................................................................................. 7 
1.3     Rationale for Study Design ................................................................................... 8 
1.4     Correlative Studies: Background ........................................................................... 8 
1.5     Inclusion of Women and Minorities ...................................................................... 10 
2.0     OBJECTIVES ......................................................................................................................... 10 
2.1     Primary Objective ................................................................................................. 10 
2.2     Secondary Objectives ............................................................................................ 10 
2.3     Correlative Objectives .......................................................................................... 10 
3.0      ON-STUDY GUIDELINES ..................................................................................................... 11 
4.0      ELIGIBILITY CRITERIA ........................................................................................................ 11 
4.1     Registration Eligibility Criteria ............................................................................. 11 
4.2     Randomization Eligibility Criteria ........................................................................ 11 
5.0     REGISTRATION/RANDOMIZATION AND STRATIFICATION ................................................... 12 
5.1     Registration Requirement ..................................................................................... 12 
5.2     Patient Registration/Randomization ..................................................................... 12 
6.0     DATA SUBMISSION AND SAMPLE SUBMISSION ................................................................... 16 
6.1     Data Submission ................................................................................................... 16 
6.2     Sample Collection and Submission....................................................................... 17 
6.3     Required Imaging Substudy (CALGB 580903) .................................................... 19 
7.0     REQUIRED DATA ................................................................................................................. 21 
8.0     TREATMENT PLAN .............................................................................................................. 22 
8.1     Drug Interactions .................................................................................................. 22 
9.0     DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY .................................................. 22 
9.1     Dose Levels for Pemetrexed ................................................................................. 22 
9.2     Pemetrexed Guidelines for Dose Modification and Management of Toxicity ..... 23 
9.3     Dose Modifications for Obese Patients ................................................................. 24 
10.0     DRUG FORMULATION, AVAILABILITY, AND PREPARATION ............................................. 24 
10.1     Pemetrexed (Alimta®) ........................................................................................ 24 
11.0     ANCILLARY THERAPY ....................................................................................................... 25 
11.1     Alliance Policy Concerning the Use of Growth Factors ..................................... 25 
12.0     CRITERIA FOR RESPONSE, PROGRESSION ......................................................................... 26 
12.1     Target Lesions ..................................................................................................... 26 
12.2     Non-target Lesions .............................................................................................. 27 
12.3     Evaluation of Best Overall Response .................................................................. 27 
12.4     Guidelines for Evaluation of Measurable Disease .............................................. 28 
12.5     Confirmation Measurement/Duration of Response ............................................ 28 
13.0     REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ...................................................... 29 
13.1     Duration of Treatment ......................................................................................... 29 
13.2     Extraordinary Medical Circumstances ................................................................ 29 
14.0     STATISTICAL CONSIDERATIONS ........................................................................................ 29 
14.1     Background and Rationale for Update #4 ........................................................... 29 
14.2     Overview of Study Design .................................................................................. 30 


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14.3     Sample Size Determination ................................................................................. 30 
14.4     Logistics & Patient Accrual ................................................................................ 31 
14.5     Analytic Methods Including Plans for Interim Analysis..................................... 31 
14.6     Statistical Consideration for Correlative Sciences .............................................. 32 
15.0     CORRELATIVE AND IMAGING SUBSTUDIES ....................................................................... 32 
15.1     SMRP and Osteopontin Levels ........................................................................... 32 
15.2     Tumor Tissue Expression of Thymidylate Synthase (TS) .................................. 32 
15.3     Analysis of Genetic Variants in the TYMS, DPYD and MTHFR Genes ........... 33 
15.4     Volumetric Tumor Measurements ...................................................................... 33 
16.0     ADVERSE EVENT REPORTING (AER) ................................................................................. 33 
16.1     CALGB 30901 Reporting Requirements ............................................................ 35 
16.2     Additional Instructions or Exclusions from CTEP-AERS Expedited Reporting 
Requirements for CALGB 30901: .................................................................................. 36 
17.0     REFERENCES ..................................................................................................................... 37 
 


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1.0 
INTRODUCTION 
1.1 
Chemotherapy for Mesothelioma 
Malignant pleural mesothelioma (MPM) is an uncommon tumor afflicting up to 3,000 patients 
annually in the United States. Most patients present with advanced disease, and treatment is 
limited to palliative chemotherapy. Only recently has the first chemotherapy regimen for 
mesothelioma, pemetrexed and cisplatin, been approved by the FDA. In a randomized phase III 
trial, treatment with pemetrexed and cisplatin was better than cisplatin alone with regard to 
response rates (41 vs. 17%), time to progression (6 vs. 4 months), and overall survival (12 vs. 9 
months) (1). The combination of pemetrexed and carboplatin is a reasonable alternative for 
patients who cannot tolerate cisplatin based on results from large phase II trials and the expanded 
access experience showing comparable response rates and survival times (2-4).  
1.2  
Duration of Therapy 
The optimal duration of first-line chemotherapy has been a long-standing question in the 
treatment of many solid tumors. Many investigators have argued that if a patient’s cancer is 
controlled and the toxicities of the treatment are manageable, then discontinuation of the therapy 
will only result in earlier tumor regrowth. On the other hand, solid tumors ultimately reach a 
response plateau at which time additional chemotherapy does not result in further tumor 
shrinkage. Furthermore, continuation of chemotherapy for prolonged periods results in 
cumulative toxicities. 
The experience in non-small cell lung cancer highlights this issue with several clinical trials 
designed to address the optimal duration of chemotherapy. In one study, patients with advanced 
NSCLC were randomized to receive paclitaxel and carboplatin for four cycles, or to continue 
that treatment until disease progression (5). No difference in survival, response rate, or quality 
of life was observed between the two study arms, yet patients on the continuation arm developed 
more peripheral neuropathy. Indeed, a meta-analysis presented at the ASCO 2008 Annual 
Meeting pooling data from 13 randomized trials demonstrated that maintenance chemotherapy 
significantly improves progression free-survival, but has minimal effect on overall survival (HR 
0.94, p=0.10) (6). Current treatment guidelines for advanced NSCLC recommend four to six 
cycles of first-line platinum based chemotherapy and then monitoring for progression.  
Another approach involves the use of a non-cross resistant regimen after completion of first-line 
therapy. The question becomes an issue of timing—does immediate treatment with a second-
line regimen improve outcomes, or should patients be allowed to recover from the first regimen 
and restart chemotherapy at the time of progression? One trial also presented at the ASCO 2008 
Meeting brought this issue to the forefront. In that study, 663 patients with advanced NSCLC 
and at least stable disease after completion of four cycles of platinum-based chemotherapy were 
randomized to receive pemetrexed or placebo (7). Treatment with pemetrexed not only 
improved PFS from 2 to 4 months, but also improved median overall survival from 10 to 13 
months. These results may be confounded by the study design, however, since only 12% of 
patients on the placebo arm ultimately received pemetrexed as second-line therapy. For 
comparison, another phase III study randomized NSCLC patients to treatment with delayed vs. 
immediate second-line therapy with docetaxel (8). While PFS was markedly improved with 
immediate docetaxel from 2.8 to 6.5 months (p<0.0001), only a trend toward improved survival 
was observed (9.1 to 11.9 months, p=0.07).  Nonetheless, when the data from the pemetrexed 
maintenance trial were added to the meta-analysis described above, the favorable effect of 
maintenance chemotherapy on overall survival became significant with a HR of 0.92 and p=0.03 
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1.3 
Rationale for Study Design 
This study aims to determine if continuing pemetrexed as “maintenance” therapy after treatment 
with a pemetrexed/platinum regimen will improve outcomes for patients with malignant pleural 
mesothelioma. This concept is based on several points: 1) Pemetrexed/cisplatin is a standard 
first-line regimen in MPM; 2) Maintenance pemetrexed improved PFS and OS in NSCLC with 
a relatively low rate of cumulative toxicity in that study; 3) A phase III trial in advanced MPM 
confirmed that treatment with pemetrexed as a second-line regimen resulted in improved 
progression free survival over best supportive care (although that trial was conducted in patients 
who had not received pemetrexed as part of their first-line therapy) (9); 4) A Dutch single arm 
study conducted in patients with mesothelioma who had at least stable disease after 6 cycles of 
pemetrexed-based chemotherapy demonstrated that maintenance therapy with pemetrexed in 
patients with mesothelioma was well tolerated, resulted in some radiologic responses, and hinted 
at improved TTP and OS (10).  
In this proposed study, patients with MPM who have a response or stable disease after four to 
six cycles of pemetrexed and cisplatin or carboplatin will be randomized to continued treatment 
with pemetrexed alone or to observation. At the time of progression, the choice of chemotherapy 
will be at the discretion of the treating physician. Many patients in the observation arm are likely 
to receive pemetrexed again which will help address the question regarding immediate vs. 
delayed therapy.  
1.4 
Correlative Studies: Background 
1.4.1 
Serum Markers 
The levels of soluble mesothelin related peptide (SMRP) and osteopontin were found to be 
elevated in patients with mesothelioma and may have a role as tumor markers (11,12). In 
prior reports, the levels of these markers were compared with those in control patients 
including those with asbestos related non-malignant pulmonary disease. Data that is 
available regarding whether these markers can be used as an adjunct to monitoring the 
disease status (such as response to chemotherapy) or estimating prognosis (such as overall 
survival) in patients with MPM is limited (13). 
1.4.2 
Tumor Thymidylate Synthase Expression and Analysis of Genetic Variants 
Pemetrexed exerts its activity through inhibition of folic acid metabolism. One of the 
enzymes critical in this metabolism is thymidylate synthase. It has been hypothesized that 
tumors over-expressing thymidylate synthase may not respond to pemetrexed as well as 
tumors having low expression of this enzyme (14). 
Expression of thymidylate synthase will be determined by immunohistochemistry using 
standard light microscope techniques. In addition, DNA will be extracted from whole blood 
collected for the analysis of genetic variants in the TYMS, DPYD, and MTHFR genes. 
These variants have been shown to affect the efficacy of therapeutics targeting thymidylate 
synthase (15). 


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1.4.3 
Novel Radiologic Techniques to Monitor Response 
Tumor measurement in patients with malignant pleural mesothelioma has been notoriously 
challenging. Rather than a rounded tumor mass that can be measured in one or two 
dimensions (as in lung tumors), mesothelioma spreads as a sheet along the pleura. This has 
led investigators to measure the pleural thickness as a surrogate. A “modified RECIST” 
system has been “qualified/validated” in which pleural thickness is measured at reproducible 
levels and the sum of the thickness measurements is used to assess response to therapy (16). 
This process remains suboptimal, especially in terms of reproducibility and assessment of 
tumor burden. 
Pass et al. have demonstrated that preoperative tumor volume is representative of T status 
in MPM and predictive of overall and progression-free survival as well as postoperative 
stage. Large volumes are associated with nodal spread and post resection residual tumor 
burden may predict outcome (17). However, lack of automated/semi-automated tools to the 
identification and measurement of tumor volumes prevents further validation of such critical 
clinical findings as well as clinical use of the volumetric technique in the diagnosis of 
mesothelioma and assessment of therapeutic response.  
Dr. Lawrence Schwartz and Dr. Binsheng Zhao, radiologists at Memorial Sloan-Kettering 
Cancer Center, have developed a three-dimensional (3D) computer method to assist in 
separation of tumor volume of MPM from its surrounding normal organs/tissues on CT 
images. By employing a priori knowledge and modeling relevant normal anatomical 
structures, they have developed a novel segmentation strategy to sequentially dissect MPM 
from its surrounding organs/tissues including chest wall, liver, spleen and lung parenchyma. 
A mathematical modeling method is used to obtain the thoracic volume by introducing a 
parabolic curve model to interpolate disconnected chest ribs on the coronal images and an 
arc interpolation algorithm to interpolate disconnected chest ribs on the axial images. An 
optimal combination of the two thoracic volumes enclosed with the connected chest ribs on 
the two view images will create a final thoracic volume (18). Internal organs such as the 
liver and spleen are automatically detected and segmented using a Gradient Vector Flow 
(GVF) snake technique that was developed for segmentation of the liver volume in a liver 
CAD project (19). In the thorax and the abdomen where relevant organs are segmented and 
removed, MPM can be separated using a thresholding method.  
To correlate with clinical outcomes, this algorithm was retrospectively applied to two 
mesothelioma clinical trials in which the patients were treated with induction chemotherapy 
followed by surgery and radiation. The clinical characteristics and outcome from 30 patients 
enrolled on these two clinical trials were compiled and the segmentation algorithm applied 
to assist in calculating tumor volumes on baseline and 2 follow-up scans (cycles 2 and 4 of 
chemotherapy). Overall survival was measured using a landmark time at three months post 
treatment start date such that all patients had already received 2 and 4 cycles of 
chemotherapy. The percent change of tumor volume from baseline to 2 cycles of 
chemotherapy was significantly associated with overall survival (Hazard Ratio: 1.90 (95% 
CI: 1.02 – 3.55), p=0.04). 


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1.5 
Inclusion of Women and Minorities 
Patients who meet the eligibility criteria will be included in this study without regard to gender, 
race, or ethnicity, which are not expected to influence response or toxicity to the treatment. 
However, gender, race and ethnicity will be analyzed as important co-variates in reporting the 
results. 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
1 
1 
0 
0 
2 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
1 
1 
0 
0 
2 
White 
12 
43 
1 
1 
57 
More Than One Race 
0 
0 
0 
0 
0 
Total 
15 
46 
1 
1 
63 
 
Accrual Rate: 
2 
pts/month 
Total Expected Accrual: 60 
Min 
63 
Max 
 
2.0 
OBJECTIVES  
2.1 
Primary Objective 
To determine if maintenance therapy with pemetrexed improves progression-free survival in 
patients with malignant pleural mesothelioma who have at least stable disease after completion 
of first-line therapy with pemetrexed plus cisplatin or carboplatin. 
2.2 
Secondary Objectives 
2.2.1 To determine if maintenance therapy with pemetrexed improves overall survival. 
2.2.2 To evaluate frequency of responses to maintenance therapy with pemetrexed. 
2.2.3 To assess toxicity of maintenance therapy with pemetrexed. 
2.3 
Correlative Objectives 
2.3.1 To assess whether serum biomarkers, including but not limited to soluble mesothelin related 
peptide (SMRP) (in epithelioid histology) and osteopontin, correlate with tumor response, 
progression free survival and overall survival.  
2.3.2 To determine whether high expression of thymidylate synthase correlates with lack of 
clinical benefit of pemetrexed (response rate, progression free survival, and overall 
survival). 
2.3.3 To determine whether specific polymorphisms in the TYMS, DPYD and MTHFR genes 
correlate with a lack of clinical benefit of pemetrexed. 
2.3.4 To determine the association between volumetric measurement of tumor response and usual 
methods of modified RECIST criteria. 


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3.0 
ON-STUDY GUIDELINES 
The following guidelines are to assist physicians in selecting patients for whom protocol therapy is 
safe and appropriate. Physicians should recognize that the following might increase the risk to the 
patient entering this protocol: 
• 
Patients with medical conditions which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient should not be enrolled. Such conditions include 
ongoing or active infection, such as HIV+ patients; inability to take oral medications; or 
psychiatric illness/social situations that would limit compliance with study requirements. 
• 
Patients with clinically significant pleural or peritoneal effusions that cannot be adequately 
managed by drainage prior to or during pemetrexed. 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin cancers and 
carcinoma in situ of the cervix. Patients are not considered to have a “currently active” second 
malignancy if they have completed therapy and have no evidence of recurrence for at least 5 
years. 
• 
Estimated life expectancy <12 weeks. 
4.0 
ELIGIBILITY CRITERIA 
4.1 
Registration Eligibility Criteria 
4.1.1 Histologic Documentation: Histologically documented malignant pleural mesothelioma, 
epithelial, sarcomatoid or mixed type, not amenable to surgical resection.  
4.1.2 Prior Treatment 
• 
Currently receiving first-line treatment with pemetrexed + platinum. Patients are to be 
registered to CALGB 30901 no later than the last day of cycle 4 of first line therapy. 
• 
Prior intracavitary cytotoxic or sclerosing therapy (including bleomycin) are acceptable. 
Prior intrapleural cytotoxic chemotherapy will not be considered systemic 
chemotherapy. 
• 
Prior surgical treatment is allowed. 
• 
Prior radiation therapy is allowed. 
4.1.3 Age ≥ 18 years 
4.1.4 Non-pregnant and non-nursing since the effects of pemetrexed on the fetus/infant are 
unknown. In addition, women of child bearing potential and men must agree to use an 
appropriate method of birth control throughout their participation in this study. Appropriate 
methods of birth control include abstinence, oral contraceptives, implantable hormonal 
contraceptives (Norplant), or double barrier methods (diaphragm plus condom). 
4.2 
Randomization Eligibility Criteria 
4.2.1 Patients with complete response, partial response, or stable disease following 4, 5 or 6 cycles 
of first-line chemotherapy with pemetrexed AND either cisplatin or carboplatin. A 
maximum of 6 cycles of chemotherapy may have been given. 
4.2.2 ECOG performance status of 0-1. 
4.2.3 Required Randomization Initial Laboratory Data: 


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Granulocytes 
≥ 1,500/ ul 
Platelet count 
≥ 100,000/ ul 
Total Bilirubin 
≤ 1.5 x ULN 
AST (SGOT) 
≤ 2 x ULN 
Calculated Creatinine Clearance * 
≥ 45 ml/min 
* 
The calculated creatinine clearance will be estimated by the Cockcroft-Gault formula as 
follows: 
 
5.0 
REGISTRATION/RANDOMIZATION AND STRATIFICATION 
Patients will be registered no later than the last day of cycle 4 of first-line therapy. Patients with CR, 
PR or SD following 4, 5 or 6 cycles of first-line therapy will then be randomized within a week of 
completing first-line treatment. The completion date of therapy is considered day 21 of cycle 4, 5 or 
6. Patients will be randomized to maintenance therapy with pemetrexed or to observation. If 
randomized to pemetrexed, treatment is to begin within 14 days following randomization.  
5.1 
Registration Requirement 
Informed Consent: The patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Human 
protection committee approval of this protocol and consent form is required. 
5.2 
Patient Registration/Randomization  
5.2.1 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation 
requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, employment, license, 
and certification) 
 
 
 
 


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Documentation Required 
IVR 
NPIVR 
AP 
A 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval     
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the 
RCR Help Desk by email at 
  
5.2.2 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System (RSS) uses 
extensive data to make a determination of whether a site has fulfilled all regulatory criteria 
including but not limited to:  
• 
an active Federal Wide Assurance (FWA) number, 
• 
 an active roster affiliation with the Lead Network or a participating organization,  
• 
a valid IRB approval, and  
• 
compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU Regulatory 


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Office. For sites using the CIRB, IRB approval information is received from the CIRB and 
applied to the RSS in an automated process. Signatory Institutions must submit a Study 
Specific Worksheet for Local Context (SSW) to the CIRB via IRBManager to indicate their 
intention to open the study locally.  The CIRB’s approval of the SSW is then communicated 
to the CTSU Regulatory Office. In order for the SSW approval to be processed, the 
Signatory Institution must inform the CTSU which CIRB-approved institutions aligned with 
the Signatory Institution are participating in a given study. 
 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the CALGB 30901 protocol page located 
on the CTSU members’ website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the Alliance link to expand, then select trial protocol CALGB 30901 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided.   
Requirements for CALGB 30901 Site Registration: 
• 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the 
NCI CIRB)  
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org (members’ area)   Regulatory Tab   
Regulatory Submission Portal 
CTSU Regulatory Office 
 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 


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• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
5.2.3 
Patient Registration through OPEN 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data.  OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website at 
https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable).  
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ side 
of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any additional 
questions contact the CTSU Help Desk at 
 
5.2.4 
Registration to Companion Studies 
There are two substudies within CALGB 30901. All patients will be registered to the 
imaging study (CALGB 580903) at the time of registration to the treatment trial, however, 
only randomized patients will participate in the imaging study. The correlative science study 
(CALGB 150912) must be offered to all patients registered to CALGB 30901 (although 
patients may opt to not participate). However, submission of samples is required only for 
those patients who are randomized.  
These substudies do not require separate IRB approval. The substudies included within 
CALGB 30901 are: 
• 
CALGB 150912 - Correlative studies in pts on CALGB 30901 (Section 6.2.1) 
• 
CALGB 580903 - Imaging study in pts on CALGB 30901 (Section 6.3) 
The instructions for submitting specimens for the correlative science companion substudy 
are in Section 6.2; the imaging study is in Section 6.3. 
If a patient answers “yes” to “My specimen(s) may be used for the genetic research 
described above,” question #1 and/or “I agree that my specimen(s) may be used for the 
research studies described above,” question #2 in the model consent, they have consented 
to participate in the correlative substudy described in Section 15. The patient should be 
registered to CALGB 150912 at the same time they are registered to the treatment trial 
(30901). Samples should be submitted per Section 6.2. 
5.2.5 
Patient Randomization through OPEN 
Following cycle 4, 5 or 6 of chemotherapy, patients with responding or stable disease will 
be randomized. Patients should be randomized within a week of completing first-line 


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pemetrexed + platinum therapy. If randomized to pemetrexed, treatment is to begin within 
14 days following randomization. The CRA will enter the patient ID number obtained at 
registration into the OPEN registration system. The patient is randomized according to the 
stratification factors, which must be entered to obtain a treatment assignment. Once the 
randomization is complete, note the patient’s treatment assignment in your records. 
5.2.6 
Stratification Factors 
First-line chemotherapy regimen: cisplatin/pemetrexed vs. carboplatin/ pemetrexed 
Histology: epithelioid vs. other 
Number of cycles received: < 6 vs. 6 cycles 
6.0 
DATA SUBMISSION AND SAMPLE SUBMISSION 
6.1 
Data Submission  
Forms should be submitted to the Alliance Statistics and Data Center at Mayo Clinic, Data 
Operations, in compliance with the Data Submission schedule below.  
• 
All data forms available online must be submitted electronically using the “Print and/or 
Submit to CALGB” button located at the bottom of the last page of each form. Forms 
submitted electronically should not be submitted by FAX or mail. 
• 
Supporting documentation (e.g., scan reports) and amended forms will be mailed to the 
Alliance Data Center, Attn: CALGB 30901 Data Manager, RO FF-3-24-CC/NW Clinic, 
200 First St, SW, Rochester, MN 55906. 
Visit the CALGB 30901 study page on the Alliance website for the most up-to-date forms. 
Form* 
Submission Schedule 
After Registration (All Patients) 
C-2123 
CALGB 30901 Pre-randomization Form 
At time of randomization or decision 
not to randomize. 
After Randomization/Baseline (Randomized Patients Only)* 
C-1938 
CALGB 30901 On-Study Form 
Within 14 days of registration 
Report 
CT and Pathology reports 
C-2000 
CALGB Solid Tumor Evaluation Form† 
C-2001 
CALGB Mesothelioma Measurement Form† 
During Treatment / Observation and Post-treatment Follow-up 
C-1941 
CALGB 30901 Adverse Event Form** 
At the end of each cycle for patients 
randomized to the treatment arm. 
 
 
 
C-1942 
CALGB 30901 Follow-up and Response Form 
Every 2 cycles for 6 months, then 
every 3 cycles for 6 months, then 
every 4 cycles months for a maximum 
of 3 years from date of randomization 
or until disease progression 
(whichever happens first). 
For patients who discontinue protocol 
therapy for reasons other than disease 
progression (including observation 
patients receiving non-protocol 
therapy), post-treatment follow-up 
C-2000 
CALGB Solid Tumor Evaluation Form† 
C-2001 
CALGB Mesothelioma Measurement Form† 
Report 
CT reports 


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should continue at the same time 
points described above. 
Note: For patients on observation or 
in post-treatment follow-up, the 
equivalent of a cycle is 3 weeks. 
After Disease Progression 
 
C-1942 
Follow-up and Response Form 
After disease progression, every 6 
months for a maximum of 3 years 
from date of randomization to report 
survival data.  
Other  
C-300 
Off Treatment Form†† 
At end of all protocol treatment (and 
before beginning non-protocol 
treatment). 
C-113 
Notification of Death 
At time of death. 
C-1001 
New Malignancy Form 
At time of diagnosis of new 
malignancy. 
C-1820 
Adverse Events Addendum Form 
Complete if additional space is 
needed to report other adverse events.  
See form for instructions.  
*Use CALGB Remarks Addenda (C-260) if additional comments are necessary or additional writing 
space is needed. If patient never starts treatment, only submit on-study data and C-300. 
**Submit AE form until all treatment related events have resolved or non-protocol treatment begins.   
†For patients randomized to the Observation Arm, the reporting period question should be marked as 
‘Post treatment’ for all measurement forms except at Baseline. 
††For patients randomized to the Observation Arm, submit if the patient begins another non-protocol 
therapy prior to progression, otherwise submit at progression as ‘Completed per protocol therapy.’ 
6.2 
Sample Collection and Submission 
The following section will provide details about how specimens will be collected, when they 
will be collected, and where they will be submitted for those randomized patients who consent 
to CALGB 150912.  
Sample Type 
Pre-
Treatment 
Prior to Cycle 3 
(Week 6) 
At Progression 
Ship To 
Tissue Block  
X 
 
 
PCO 
Whole Blood (lavender top)  
1 x 10 mL 
 
 
PCO 
Plasma (lavender top) 
1 x 6 mL 
1 x 6 mL 
1 x 6 mL 
PCO 
Serum (red/gray SST) 
1 x 6 mL 
1 x 6 mL 
1 x 6 mL 
PCO 
6.2.1 
Correlative Substudy Sample Collection 
For the study of genetic variants, one 10 ml tube of blood will be collected prior to treatment. 
Initial blood samples collected for evaluation of SMRP and Osteopontin levels will be 
obtained within 7 days prior to beginning the first cycle of therapy with maintenance 
pemetrexed (or the observation period). The time and day of sample acquisition is not 
critical as long as it occurs within the week prior to receiving any treatment. A second 
sample will be collected within 2 days of beginning cycle 3 (week 6 for observation 


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patients). A third sample will be drawn when the patient’s tumor progresses while on 
pemetrexed therapy or observation. This third sample should be drawn prior to initiation of 
any additional chemotherapy.   
Blood Sample Collection 
• 
For analysis of genetic variants, collect one 10 ml lavender top (EDTA) tube of whole 
blood. The tube should be inverted 8-10 times to mix the tube additive and then 
refrigerated until shipped. Samples should be packaged to prevent breakage and shipped 
on a cold pack for processing. Samples should be shipped via overnight courier the 
same day they are collected. 
• 
For plasma measurement of osteopontin collect one 6 ml lavender top (EDTA) tube of 
peripheral or central venous blood. Gently invert the tube 8 times to mix the additive 
and immediately centrifuge at 1300g or 3000 RPM for 10 minutes at room temperature. 
After centrifugation, aspirate plasma without disturbing cells, then place 1 ml aliquots 
into 2.0 ml cryogenic vials (see details below)*. Store the vials at -70°C or colder until 
shipping. Ship samples within 30 days on dry ice.  
• 
For serum measurement of SMRP collect one 6 ml red/gray serum separator tube (tiger 
top) of peripheral or central venous blood. Gently invert 5 times to mix clot activator 
with blood. Let blood clot for 30 minutes. Observe a dense clot. Centrifuge at 1300g or 
3000 RPM for 10 minutes. After centrifugation, place 1 ml aliquots of serum into 2.0 
ml cryogenic vials (see details below)*. Store the vials at -70°C or colder until shipping. 
Ship samples within 30 days on dry ice. 
 
*Cryovial Choices: Some examples of acceptable 2.0 ml cryovials are: Nalgene (Cat 
#5012-0020), Fisher (Cat #05-669-57), Corning (Cat #430488), VWR (Cat #16001-
102). 
• 
Label all samples with patient’s initials, (last, first, middle), patient ID number, study 
number, date drawn and type of specimen collected (e.g., serum, whole blood). 
6.2.2 
 Pathology Specimen 
For patients who consent, institutions will submit the pathology report and an adequate sized 
paraffin block from the core biopsy. The Alliance has instituted special considerations for 
the small percentage of hospitals whose policies prohibit release of any block. If, due to 
institutional policy, a block cannot be sent, please contact the Alliance Biorepository for 
alternative instructions.  
6.2.3 
Specimen Registration, Tracking and Submission Instructions 
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL: 
http://bioms.allianceforclinicaltrialsinoncology.org using most standard web browsers 
(Safari, Firefox, Internet Explorer). For information on using the BioMS system, please refer 
to the ‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, and 
training videos. To report technical problems, such as login issues or application errors, 
please contact: 
For assistance in using the application or questions or 
problems related to specific specimen logging, please contact: 
 


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After logging collected specimens in BioMS, the system will create a shipping manifest. 
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
Shipment of samples 
• 
All samples should be labeled with study number, patient ID number, patient initials, 
sample collection date and time, and be accompanied by the completed specimen 
submission shipping manifest which will be generated by BioMS.  
Note for CRA – The following PHI must be removed or blacked out for all specimens or 
reports: signature, name, date of birth, other identifying information, except initials and 
study identification number. 
• 
All samples should be shipped to the Alliance Biorepository at Ohio State. 
• 
Specimens may be sent to the Alliance Biorepository on Monday through Thursday for 
next day delivery. The Bank cannot receive specimens on Saturdays, Sundays or 
holidays. Do not send specimens the day before a holiday. 
• 
The institution is expected to pay the cost of mailing specimens and will be reimbursed 
through capitation fees set for each individual study. 
• 
Arrange for express courier pick-up through your usual institutional procedure. Ship 
specimens to the address below: 
Alliance Biorepository at Ohio State 
Innovation Centre 
 
 
 
On the day that specimens are sent to the specimen bank, please contact the bank by phone 
or e-mail to notify what is being sent and when the shipment is expected to arrive. 
6.3 
Required Imaging Substudy (CALGB 580903)  
6.3.1 
CT Imaging Requirement 
Contrast enhanced CT scans will be obtained at the following time points for all patients: 
• 
Baseline: Within one month before patient randomization 
• 
During Treatment/Observation: Every 2 cycles for 6 months, then every 3 cycles for 6 
months, then every 4 cycles until disease progression for a maximum of 3 years from 
the date of randomization. 
• 
Follow-Up (after progression): None 
Contrast enhanced CT scans will be performed using 2.5 mm cuts. In the event that a site is 
unable to obtain a 2.5 mm cut, 5 mm cuts will also be permitted.  
Optimal Technique: The requirements listed below are to be used for the chest CT scan 
whenever possible. 
• 
Scanning mode: Helical 
• 
Patient position: Supine, arms up 
• 
Scan extent: Thoracic inlet through the most inferior extent of the pleural spaces 
• 
Scan time: Single breath-holding period, in full inspiration 


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• 
Section thickness: 1.5 mm or less 
• 
Enhancement: Intravenous contrast unless contraindicated by allergy 
• 
Reconstruction: Contiguous or overlapping sections; no gaps 
Minimum CT requirements are listed below. 
• 
Scanning mode: Helical 
• 
Patient position: Supine 
• 
Scan extent: Thoracic inlet through the most inferior extent of the pleural spaces 
• 
Scan time: Single breath-holding period, in full inspiration 
• 
Section thickness: 5mm or less 
• 
Enhancement: Preferred but not mandatory 
• 
Reconstruction: Contiguous or overlapping sections; no gaps 
6.3.2 
CT Data Submission 
Images must be submitted to the Alliance Imaging Core Lab within 3 business days once 
the image acquisition is completed at the site. 
Send de-identified digital CT images in DICOM format on a CD or electronically via 
Web or FTP to the Alliance Imaging Core Lab at The Ohio State University. BMP 
files, JPG files or hard copies (films) are not acceptable.  
Sites interested in sending images electronically via Web or FTP to the Imaging Core Lab 
should send an e-mail to 
 for standard Web or FTP 
access information. 
If the electronic data transfer cannot be achieved at sites, CT scans may be sent on a CD to 
the Imaging Core Lab at: 
Alliance Imaging Core Laboratory 
Attn: CALGB30901 
Wright Center of Innovation 
The Ohio State University 
 
 
 
 
 
Institutions must complete the CALGB 30901 Radiology Submission Form (C-1958) and 
fax or mail it to the Imaging Core Laboratory within 24 hours of submitting the baseline 
scan. The Imaging Laboratory will acknowledge receipt of the submission by e-mail within 
24 hours of receipt of the materials, excluding holidays and weekends. 


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7.0 
REQUIRED DATA 
Guidelines for Pre-Study Testing 
To be completed within 16 DAYS before randomization: 
- All blood work 
To be completed within 28 DAYS before randomization: 
- 
Any scan which is utilized for tumor measurement  
 
Tests & Observations 
Prior to 
Randomization 
Every 3 weeks 
(Pemetrexed arm only) 
Every 6 weeks 
(Both arms) 
History and Progress Notes 
X 
X 
X 
Physical Examination 
X 
X 
X 
Pulse, Blood Pressure 
X 
X  
X 
Weight 
X 
X 
X 
Height 
X 
X 
X 
BSA† 
X 
X 
X 
Performance Status 
X 
X 
X 
Tumor Measurements 
X 
 
X 
Drug Toxicity Assessment 
 
X 
 
Laboratory Studies 
 
 
 
CBC, Differential, Platelets* 
X 
X 
X 
Serum Creatinine, BUN* 
X 
X 
X 
Serum Electrolytes* 
X 
X 
X 
SGOT, Alk.Phos., Bilirubin* 
X 
X 
X 
Serum or urine HCG** 
X 
 
 
Correlative Substudy 
B 
 
B 
Pathology Block 
C 
 
 
Staging 
 
 
 
Chest and upper abdomen CT 
scan w/ contrast*** 
A 
 
A†† 
Imaging Substudy 
D 
 
D†† 
*  
Pre-study laboratory tests may be used for the day 1 of Cycle 1 requirements if obtained within 
14 days of treatment.  
** 
If female and of childbearing potential. 
*** CT Scan requirements for this protocol: 
Optimal Technique: The requirements listed below are to be used for the chest CT scan 
whenever possible. 
• 
Scanning mode: Helical 
• 
Patient position: Supine, arms up 
• 
Scan extent: Thoracic inlet through the most inferior extent of the pleural spaces 
• 
Scan time: Single breath-holding period, in full inspiration 
• 
Section thickness: 1.5 mm or less 
• 
Enhancement: Intravenous contrast unless contraindicated by allergy 
• 
Reconstruction: Contiguous or overlapping sections; no gaps 


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† 
It is not necessary to change the dose of pemetrexed unless the calculated dose changes by ≥ 
10%. 
†† 
Every 2 cycles for 6 months, then every 3 cycles for 6 months, then every 4 cycles until disease 
progression for a maximum of 3 years from the date of randomization. 
A 
CT chest and any other known site of extrathoracic metastasis: Use intravenous contrast when 
possible. CT scans should be performed with 2.5 mm cuts for volumetric assessment (See 
section 15.4).  
B 
For patients who consent, blood will be collected according to Section 6.2.1. 
C 
For patients who consent, a block should be submitted per Section 6.2.2. 
D 
For more information on the imaging substudy (CALGB 580903) please refer to Section 6.3. 
8.0 
TREATMENT PLAN 
Questions regarding treatment should be directed to Dr. Arkadiusz Dudek. 
Patients will be registered no later than the last day of cycle 4 of first-line therapy. Patients with CR, 
PR or SD following 4, 5 or 6 cycles of first-line therapy will then be randomized within a week of 
completing first-line treatment. Patients will be randomized to maintenance therapy with pemetrexed 
or to observation. If randomized to pemetrexed, treatment is to begin within 14 days following 
randomization.  
Patients assigned to the treatment arm will receive pemetrexed 500 mg/m2 IV over 10 minutes (or 
per institutional guidelines) every three weeks. Patients will continue treatment until disease 
progression or excess toxicity. At the time of disease progression, the choice of therapy is left to the 
physician’s discretion. 
Pemetrexed Premedications: 
Folic Acid: Oral folic acid (0.35 - 1 mg/day) starting at least 1 week before the first pemetrexed 
dose and continue for 21 days after the last dose of pemetrexed. 
Vitamin B12: Vitamin B12 1000 mcg IM injection. A vitamin B12 injection must be administered at 
least 1 week before the initial pemetrexed dose and repeated every 9 weeks while on pemetrexed 
until 21 days after last dose of pemetrexed. 
Dexamethasone: Dexamethasone (4 mg orally or equivalent) BID the day before, the day of, and 
the day after each dose of pemetrexed, for a total of 6 doses per cycle. 
8.1 
Drug Interactions 
Patients should avoid taking NSAIDs for a period of 5 days before, the day of, and 2 days after 
pemetrexed administration. If patients must be on NSAIDs, they are to be monitored closely for 
toxicities. 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
The starting dose of pemetrexed is 500mg/m2, even if the patient required a pemetrexed dose 
reduction during platinum doublet therapy.  
If multiple toxicities are evident and more than one of the dose modifications applies, use the most 
stringent dose reduction (i.e., the greatest dose reduction). Dose may not be re-escalated once it has 
been reduced.  
9.1 
Dose Levels for Pemetrexed 
Treatment should be discontinued in patients requiring a dose level reduction beyond level -2. 
Dose levels for pemetrexed are below. 


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Dose Level 
Pemetrexed 
0 
500 mg/m2 
-1 
375 mg/m2 
-2 
250 mg/m2 
9.2 
Pemetrexed Guidelines for Dose Modification and Management of Toxicity  
9.2.1 
GI Toxicity 
Grade 3 or 4 diarrhea despite antidiarrheal medication and prophylactic vitamin 
supplementation at any time during a cycle: Delay pemetrexed until diarrhea resolves to 
≤ grade 2. Resume pemetrexed when diarrhea resolves to ≤ grade 2 at one dose level lower 
than the previous dose for all subsequent cycles. If diarrhea has not improved to ≤ grade 2 
within 3 weeks, discontinue pemetrexed. 
Grade 3 or 4 oral mucositis despite prophylactic vitamin supplementation at any time 
during a cycle: Delay pemetrexed and resume when mucositis resolves to ≤ grade 2 at one 
dose level lower than the previous dose for all subsequent cycles. If oral mucositis has not 
improved to ≤ grade 2 within 3 weeks, discontinue pemetrexed therapy. 
9.2.2 
Hematologic Toxicity 
For ANC <1,500 or platelets <100,000 on day 1, delay treatment with pemetrexed until 
ANC ≥1,500 and platelets ≥100,000, then resume pemetrexed at one dose level lower for 
all subsequent doses. If treatment is delayed for ≥ 3 weeks, discontinue all protocol 
treatment. 
For febrile neutropenia occurring at any time during a cycle, decrease pemetrexed by one 
dose level for all subsequent doses. 
9.2.3 
Calculated CrCl < 45 ml/min 
If creatinine clearance is < 45 ml/min, delay pemetrexed until CrCl ≥45 ml/min. When CrCl 
improves to ≥ 45 ml/min, resume pemetrexed at the previous doses. If CrCl remains < 45 
ml/min at 3 weeks, discontinue pemetrexed therapy. 
9.2.4 
Clinically Significant Effusions 
For patients who develop clinically significant pleural or pericardial effusions (on the basis 
of symptoms of physical examination) during therapy, consideration should be given to 
draining the effusion prior to the next dose of pemetrexed. However, in the opinion of the 
treating physician, if the effusion represents progression of disease, the patient should 
discontinue protocol therapy. 
9.2.5 
Skin Toxicity 
Grade 3 or 4: For grade 4 skin toxicity, discontinue pemetrexed. For Grade 3, hold 
pemetrexed until toxicity improves to ≤ grade 1, then resume pemetrexed at the previous 
dose level. For recurrent grade 3 skin toxicity, hold pemetrexed until toxicity improves to ≤ 
grade 1, then resume pemetrexed with one dose level reduction. If pemetrexed is held for 
skin toxicity for 3 weeks, discontinue pemetrexed. 


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9.2.6 
Hypersensitivity Reactions 
For grade 3 or 4 allergic reactions or anaphylaxis thought to be due to pemetrexed, 
discontinue pemetrexed. 
9.2.7 
Other Non-Hematologic Grade 3 Toxicity  
Excluding fatigue and anorexia: Hold pemetrexed until toxicity improves to       ≤ grade 
2, then resume pemetrexed with one dose level reduction. If pemetrexed is held for 3 weeks, 
discontinue therapy with pemetrexed. 
For recurrent other non-hematologic grade 3 toxicity: Discontinue all protocol therapy. 
9.2.8 
Other Non-Hematologic grade 4 toxicity (not described above):  
Discontinue pemetrexed therapy. 
9.3 
Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight. Therefore, all dosing is to be determined solely 
by (1) the patient’s BSA as calculated from actual weight or (2) actual weight without any 
modification unless explicitly described in the protocol. This will minimize the risk of 
calculation error and the possible introduction of variability in dose administration. Failure to 
use actual body weight in the calculation of drug dosages will be considered a major 
protocol deviation. Physicians who are uncomfortable with administering chemotherapy dose 
based on actual body weight should not enroll obese patients on Alliance protocols. 
10.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
• 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe disposal 
of chemotherapeutic agents in a self-contained, protective environment. 
• 
Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection 
USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial entry to minimize 
the risk of bacterial contamination. 
• 
The total administered dose of chemotherapy may be rounded up or down within a range of 5% 
of the actual calculated dose. 
• 
It is not necessary to change the doses of any of the agents used in this trial unless the calculated 
dose changes by ≥ 10%. 
10.1 
Pemetrexed (Alimta®) 
Please refer to the FDA approved package insert for additional information 
Availability 
Pemetrexed is available commercially as a lyophilized powder for reconstitution in single-use 
vials containing 500 mg pemetrexed. 
Storage and Stability 
Intact vials of pemetrexed should be stored at room temperature. The reconstituted and further 
diluted solutions for infusions are stable for up to 24 hours when refrigerated or stored at room 
temperature. 
Preparation 


CALGB 30901 
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Each 500 mg of pemetrexed is reconstituted with 20 mL of 0.9% sodium chloride for injection, 
resulting in a concentration of 25 mg/mL. The desired dose should be withdrawn and further 
diluted in 100 mL of 0.9% sodium chloride for injection, for IV infusion. 
Administration 
Pemetrexed will be administered as a 10 minute IV infusion every 21 days  
Toxicities 
The most common toxicities reported with pemetrexed to date include myelosuppression, GI 
toxicities, rash and fatigue. Neutropenia is more common than thrombocytopenia, and it is 
minimized with vitamin supplementation. Specifically, folic acid and Vitamin B12 starting 
before pemetrexed and continuing throughout pemetrexed therapy are recommended. It is 
thought that severe pemetrexed toxicity is due to a subclinical folate deficiency, as may be 
documented by an elevated plasma homocysteine. Similarly, diarrhea and mucositis are also 
minimized with the use of folic acid and B12. Single agent pemetrexed was associated with 
nausea and vomiting in approximately 30% of patients. In the majority of patients, nausea and 
vomiting were ≤ grade 2 severity. The incidence and severity of pemetrexed-induced rash 
appears to be decreased with the administration of dexamethasone, beginning the day before 
pemetrexed. Fatigue, grade 1-3 severity, is also common. 
Drug Interactions 
As is the case with methotrexate, the potential exists for various drugs (e.g., NSAIDs, 
probenecid, salicylates, sulfonamides) to delay pemetrexed renal clearance and increase toxicity. 
11.0 ANCILLARY THERAPY 
• 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc., when appropriate. The reason(s) for treatment, dosage, and the 
dates of treatment should be recorded on form C-260. 
• 
Treatment with hormones or other chemotherapeutic agents may not be administered except for 
steroids given for adrenal failure; hormones administered for non-disease-related conditions 
(e.g., insulin for diabetes); and intermittent use of dexamethasone as an antiemetic or as 
premedication for pemetrexed.  
• 
Palliative radiation therapy may not be administered during protocol therapy. Any patients 
requiring palliative radiation therapy will be removed from protocol therapy. 
• 
Therapy for severe diarrhea (grade 3 or 4) may require supportive measures such as hydration, 
octreotide, electrolyte repletion and antidiarrheals as clinically appropriate. If diarrhea is severe 
(requiring intravenous rehydration) and/or associated with fever or severe neutropenia, 
physicians should give consideration to prescribing broad-spectrum antibiotics. 
11.1 
Alliance Policy Concerning the Use of Growth Factors 
11.1.1 Epoetin (EPO) 
Use of epoetin or darbepoetin is permitted at the discretion of the treating physician. When 
used, the administration of erythropoiesis-stimulating agents should be consistent with the 
approved indication for patients receiving chemotherapy as described in current product 
literature. 


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11.1.2 Filgrastim (G-CSF), Sargramostim (GM-CSF) and Pegfilgrastim 
1. Filgrastim (G-CSF), sargramostim (GM-CSF), or pegfilgrastim may be used according 
to ASCO guidelines. 
2. If filgrastim, sargramostim or pegfilgrastim are used, they must be obtained from 
commercial sources.  
12.0 CRITERIA FOR RESPONSE, PROGRESSION 
For the purposes of this study, patients should be reevaluated every six weeks (2 cycles) for 6 months, 
then every 9 weeks (3 cycles) for 6 months and then every 12 weeks (4 cycles) until disease 
progression for a maximum of 3 years from date of registration. In addition to a baseline scan, 
confirmatory scans should also be obtained at least four weeks following initial documentation of 
objective response. 
12.1 
Target Lesions 
All measurable lesions up to a maximum of 5 lesions representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repetitive measurements (either by imaging techniques or clinically). 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension as ≥ 10 mm with CT scan. A lymph node must be ≥ 15 mm in short axis by CT scan 
in order to be considered pathologically enlarged and measureable. All measurements must be 
recorded in millimeters. A sum of the diameters (long diameter (LD) for all non nodal target 
lesions and short axis for nodal lesions) will be calculated and reported as the baseline sum LD. 
The baseline sum of all diameters will be used as reference to further characterize the objective 
tumor response of the measurable dimension of the disease. 
In patients with pleural mesothelioma the typical mesothelial “rind” should be measured on 3 
separate levels at least 2 cm apart, perpendicularly from the chest wall on a given cut. Each 
level should be measured in two different places (please see fig 1). The three rind thicknesses 
should be recorded for a given level and compared on subsequent scans. Clear anatomic 
landmarks should be recorded carefully to ensure consistency from scan to scan. At least one 
level should have a measurement ≥ 1.5 cm. Pleural areas where the initial thickness is less than 
1 cm should not be used as evaluation measurement. 
 
 
 
 
 
 
 
 
 
A sum of the measurements of the pleural rind obtained at 3 different levels should be calculated 
and reported as the baseline sum LD. 
These modified RECIST criteria have been previously validated in patients with mesothelioma 
(16). Response assessment using these methods has been found to be a greater clinical predictor 
Figure 1. Measurement of mesothelioma 
rind. The typical mesothelioma rind should 
be measured in 2 different places 
(yellow/white lines) perpendicularly from 
the chest wall. These measurements should 
be performed at 3 anatomic levels at least 2 
cm apart.  


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for survival in patients with mesothelioma than a method of longest diameter to assess pleural 
thickness. 
12.1.1 Complete Response: Disappearance of all target lesions. Changes in tumor measurements 
must be confirmed by repeat studies performed no less than 4 weeks after the criteria for 
response are first met. 
12.1.2 Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions taking as reference the baseline sum LD. Changes in tumor measurements must be 
confirmed by repeat studies performed no less than 4 weeks after the criteria for response 
are first met. 
12.1.3 Progression (PD): At least a 20% increase in the sum of the diameters of target lesions 
taking as reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions. 
12.1.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD taking as reference the smallest sum of the diameters since the treatment 
started. Patients having a documented response with no reconfirmation of the response will 
be listed with stable disease. 
12.2 
Non-target Lesions 
All other lesions (or sites of disease) not included in the “target disease” definition should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are not 
required and these lesions should be followed as “present” or “absent.” 
12.2.1 Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
12.2.2 Non-complete response (non-CR)/Non-progression (non-PD): Persistence of one or 
more non-target lesion and/or maintenance of tumor marker level above the upper limits 
of normal. 
12.2.3 Progression (PD): Appearance of one or more new lesions. Unequivocal progression of 
existing non-target lesions. Although a clear progression of non-target lesions is 
exceptional, in such circumstances, the opinion of the treating physician should prevail and 
the progression status should be confirmed later on by the study chair. 
12.3 
Evaluation of Best Overall Response 
The best overall response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). In general, the patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria (see Section 12.5). 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 


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Any 
Any 
Yes 
PD 
Note: 
• 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration” on the Off-treatment Form (C-300) under “other.” Every effort 
should be made to document the objective progression even after discontinuation of 
treatment. 
• 
Conditions that may define early death include patients that have died without 
documentation of disease progression and before it was time to conduct the first tumor 
reassessment. Inevaluable patients are defined as not having received protocol treatment 
(regardless of how much was received) and no follow-up assessment completed before 
initiation of alternative treatment. 
• 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
12.4 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
12.4.1 Clinical Lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended. 
12.4.2 Chest X-ray: Lesions on chest X-ray are not acceptable as measurable lesions. A CT scan 
of the chest (with abdomen and pelvis if needed) must be used to evaluate measurable 
disease in this trial. For pelvic and/or abdominal lesions an MRI may be used to evaluate 
measurable disease. The imaging modality used to determine the initial measurement 
should continue to be used consistently for subsequent measurement evaluations. 
12.4.3 Conventional CT of the chest should be performed with contrast if possible and with cuts 
of 2.5 mm in slice thickness contiguously (see section 6.3). Spiral CT is preferred. CT 
scans of the abdomen, and pelvis may also be performed using standard slice thickness (5 
mm). 
12.4.4 Endoscopy and laparoscopy for objective tumor evaluation has not yet been fully and 
widely validated. Their uses in this specific context require sophisticated equipment and a 
high level of expertise that may only be available in some centers. Therefore, the utilization 
of such techniques for objective tumor response should be restricted to validation purposes 
in reference centers. However, such techniques can be useful to confirm complete 
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12.5 
Confirmation Measurement/Duration of Response 
12.5.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat studies that should be performed no less than four weeks after the criteria for 
response are first met. In the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of six to eight weeks. 
12.5.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively documented. 
12.5.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment started. 
13.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
13.1 
Duration of Treatment 
13.1.1 CR, PR, or SD: Continue treatment until the appearance of disease progression. 
13.1.2 Disease Progression: Give a minimum of two cycles of therapy. Remove from protocol 
therapy any patient with rapid disease progression. Document details, including tumor 
measurements, on C-2000. 
13.2 
Extraordinary Medical Circumstances  
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Notify the Study Chair. 
• 
Document the reason(s) for discontinuation of therapy on Form C-260. 
• 
Follow the patient for survival, secondary malignancy, and new primaries. 
14.0 STATISTICAL CONSIDERATIONS 
14.1 
Background and Rationale for Update #4 
CALGB 30901 was activated on 4/15/2010. In the original protocol design (30901-01, 30901-
02 and 30901-03), we assumed that arm A (observation) would produce a median PFS of 3 
months during the maintenance phase. Arm B (experimental) would have a 67% improvement 
in median PFS to 5 months. Under constant hazards, this corresponds to a hazard ratio λA/λB= 
1.67. With 90 eligible patients (45 per arm) randomized to Arm A and Arm B with a 1:1 
allocation and an accrual rate of 4 randomized patients per month and an additional follow-up 
of 12 months after the enrollment of the last patient, the study had approximately 86% to reject 
the null hypothesis λA/λB = 1 when the true λA/λB= 1.67 using a log rank test at a 1-sided 


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significance level of 0.10. With an allowance of 5% ineligibility/cancellation rate, a maximum 
of 96 (90 eligible) patients, or 48 (45 eligible) per arm, were to be accrued. 
As of November 18, 2014, 38 out of 55 registered patients were randomized. In the last 12 
months, the registration rate has been approximately 1.5 patients per month and the 
randomization rate is approximately 1 patient per month. The accrual rate is lower than we wish 
due to rarity of malignant pleural mesothelioma and existing, although unproven, clinical care 
patterns of offering maintenance therapy. The purpose of this amendment is to reduce the 
number of randomized patients by targeting a bigger effect size while maintaining the same level 
of Type I error in the original design. Instead of targeting a 2-month increase in median PFS, 
the amendment is looking for a 3-month increase in median PFS, which corresponds to a hazard 
ratio λA/λB = 2. We believe that a 3-month increase relative to observation in median PFS is 
justifiable for malignant mesothelioma patients who have achieved stable disease after the first 
line therapy. The interim analysis plan has been changed accordingly to have a futility test 
conducted after half of the total events have been observed. As a result, a maximum of 63 
patients (60 eligible) after achieving stable disease from the first line chemotherapy will be 
randomized. The valuable data collected from this randomized phase II trial will help us to 
decide if a randomized phase III trial is worthy to pursue in the future. 
14.2 
Overview of Study Design 
This will be a randomized phase II study with a primary endpoint of progression free survival. 
All patients will be treated initially with pemetrexed plus either cisplatin or carboplatin at the 
discretion of the treating physician. Patients documented to have a complete or partial radiologic 
response, or stable disease after completion of 4, 5 or 6 cycles will be eligible for enrollment. 
Patients will be stratified by first-line regimen (cisplatin vs. carboplatin) and histologic subtype 
(epithelioid vs. other) and randomly assigned to Arm A or Arm B with 1:1 allocation using a 
permutated block scheme (20). Arm A will be monitored for progression. Arm B will continue 
on chemotherapy with pemetrexed until disease progression. All patients will be followed for a 
maximum of 3 years from the date of randomization. The primary endpoint will be progression 
free survival, which is the time from patient randomization to disease progression or death from 
any cause, whichever comes first. An interim analysis is planned when accrual reaches 28 events 
(or 50% of information). Secondary objectives include (1) to determine if maintenance therapy 
with pemetrexed improves overall survival; (2) to evaluate frequency of responses to 
maintenance therapy with pemetrexed; (3) to assess toxicity of maintenance therapy with 
pemetrexed; (4) to assess whether biomarkers correlate with disease status; and (5) to determine 
the association between volumetric measurement of tumor response and usual methods of 
modified RECIST criteria. 
CT scans will be performed in both arms every 6 weeks for 6 months, then every 9 weeks for 6 
months and then every 12 weeks until disease progression for a maximum of 3 years from the 
date of randomization. The choice of chemotherapy regimen at the time of progression is at the 
discretion of the physician. Specifically, patients in Arm A would be allowed to receive 
treatment with pemetrexed at that time.  
14.3 
Sample Size Determination 
In a recent phase III trial, treatment with pemetrexed and cisplatin had a median progression free 
survival (PFS) of 6 months and median overall survival (OS) of 12 months (1).  For the purpose 
of sample size determination, we assume that (i) arm A will produce a median PFS of 3 months 
during the maintenance phase. Arm B will have a 67% improvement in median PFS to 5 months. 
Under constant hazards, this corresponds to a 3 month PFS of 50% for Arm A and 66% for the 
experimental arm (Arm B) and a hazard ratio λA/λB= 1.67; (ii) 90 eligible patients (45 per arm) 


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will be randomized to Arm A and Arm B with 1:1 allocation; (iii) an accrual rate of 4 randomized 
patients per month and an additional follow-up of 12 months after the enrollment of the last 
patient; (iv) a planned look at 50% information. Using a log rank test at a 1-sided significance 
level of 0.10, the study has approximately 86% power to reject the null hypothesis λA/λB = 1 and 
accept the alternative hypothesis λA/λB > 1 when the true λA/λB = 1.67. We will closely monitor 
the first 12 randomized patients on Arm B for treatment related adverse events. If 4 or more out 
of the 12 patients develop grade 3 or higher drug related adverse events, the study team will 
either recommend a reduction in the starting dose or permanently terminate the study. 
14.3.1 Amended Sample Size Determination (Effective 01/15/15) 
In a recent phase III trial, treatment with pemetrexed and cisplatin had a median progression 
free survival (PFS) of 6 months and median overall survival (OS) of 12 months (1).  For the 
purpose of sample size determination, we assume that (i) arm A will produce a median PFS 
of 3 months during the maintenance phase. Arm B will have a 100% improvement in median 
PFS to 6 months. Under constant hazards, this corresponds to a 3 month PFS of 50% for 
Arm A and 70.7% for the experimental arm (Arm B) and a hazard ratio λA/λB= 2; (ii) 60 
eligible patients (30 per arm) will be randomized to Arm A and Arm B with 1:1 allocation; 
(iii) an registration rate of 2 patients per month and an additional follow-up of 6 months 
after the enrollment of the last patient; (iv) a planned look at 50% information. Using a log 
rank test at a 1-sided significance level of 0.10, the study has approximately 91% power to 
reject the null hypothesis λA/λB = 1 and accept the alternative hypothesis λA/λB > 1 when the 
true λA/λB = 2. 
14.4 
Logistics & Patient Accrual  
With allowance of 5% ineligibility and an expected 70% initially registered patients remaining 
progression free after 4, 5, or 6 cycles of combination therapy, we expect to register 137 patients 
and to randomize 96 patients. Once 96 patients (90 eligible) have been accrued, a notice 
suspending accrual will be issued to the Group via an e-mail broadcast announcing termination 
of accrual effective within 10-14 days. On average, CALGB has accrued approximately 3-8 
patients per month in mesothelioma trials. The three most recent mesothelioma trials (CALGB 
30101, 30107 and 30307) accrued 5-8 patients per month. Assuming an accrual rate of 4 
randomized patients per month, we expect target accrual will be met after approximately 3 years. 
14.4.1 Amended Logistic and Patient Accrual (Effective 01/15/15) 
With allowance of 5% ineligibility and an expected 67% initially registered patients 
remaining progression free after 4, 5, or 6 cycles of combination therapy, we expect to 
register 94 patients and to randomize 63 patients. Once 63 patients (60 eligible) have been 
randomized, a notice suspending accrual will be issued to the Group via an e-mail broadcast 
announcing termination of accrual effective within 10-14 days. On average, CALGB has 
accrued approximately 3-8 patients per month in mesothelioma trials. The three most recent 
mesothelioma trials (CALGB 30101, 30107 and 30307) accrued 5-8 patients per month. 
CALGB 30901 was activated on 4/15/2010. As of November 18, 2014, a total of 55 patients 
were registered and 38 patients were randomized after achieving stable disease of the first 
line chemotherapy. Assuming that 2 patients are registered per month, we expect 
approximately an additional 20 months after Update #4 is issued to reach the target accrual.  
14.5 
Analytic Methods Including Plans for Interim Analysis 
Interim analysis for futility will be conducted when we have 28 cumulative events (50% 
information) on both arms. As of November 18, a total of 23 events have been observed. Since 
this is a relatively small randomize phase II trial, interim analysis will focus on testing futility. 


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At the futility analysis, we will compare the distribution of the PFS of the experimental with the 
standard arm. If the observed hazard ratio (experimental/standard) is greater than or equal to 1.0, 
then trial will be terminated early at the interim analysis for futility (i.e., the experimental arm 
will be considered ineffective in this disease population) and the results will be reported. If the 
observed hazard ratio of the experimental arm relative to the standard arm is less than 1.0, then 
the trial will continue to the full target accrual. Early stopping for futility using this rule is found 
to result in minimal loss of power (less than 2%) for the primary hypothesis test (21). 
The primary analysis will include all randomized patients but exclude ineligible patients or 
patients who are canceled from the study before receiving any protocol treatment. 
Progression free survival (PFS) is defined as the time from registration to disease progression 
or death of any cause, whichever comes first. Overall survival (OS) is defined as the time from 
registration to death of any cause. The primary analysis of comparing the patients continued on 
chemotherapy with pemetrexed (Arm B) relative to the patients discontinued from 
chemotherapy (Arm A) will be conducted using one-sided stratified log rank test with a 
significance level of approximately 0.10 corresponding to standardized Z statistics boundary of 
1.316. 
The product limit estimator developed by Kaplan and Meier will be used to graphically describe 
PFS and OS (22). From these product limit estimates, median PFS, median OS, 3-month PFS, 
12-month OS rate and their 95% confidence intervals will be estimated for patients randomized 
to each arm. Cox proportional hazards model (23) will be used to estimate the hazard ratios and 
their 95% confidence intervals of the experimental regimen relative to the control group with 
and without adjusting for baseline prognostic factors. As an exploratory analysis, survival 
endpoints of the two arms will be compared using log rank test (24). The frequency of best 
response (CR+PR) to each arm will be tabulated and its 95% exact binomial confidence intervals 
will be computed. Response rates (including complete and partial response) will be tested using 
Fisher’s exact test (25). Gender, race and ethnicity will be analyzed as covariates and these 
results will be reported. Frequencies of toxicities will be tabulated for patients on maintenance 
therapy with pemetrexed. 
14.6 
Statistical Consideration for Correlative Sciences 
The correlation of PFS and OS with serum biomarkers, soluble mesothelin related peptide 
(SMRP) and osteopontin, and their changes with treatment will be examined using a log rank 
test for categorical variables and using Cox’s proportional hazard model for continuous variables 
after adjusting for other prognostic factors. The optimal threshold for these biomarkers will be 
determined univariately using maximally selected log rank test with adjusted p-values. The 
correlation of PFS, OS, RR with thymidylate synthase expression will be examined similarly. 
The Mann-Whitney U test or Fisher’s exact test will be applied as appropriate to assess 
differences or proportions of genetic data for TYMS, DPYD and MTHFR genes. Tumor 
response classification using volumetric measurement will be compared to usual methods of 
modified RECIST criteria and the level of agreement will be obtained using the kappa statistic. 
15.0 CORRELATIVE AND IMAGING SUBSTUDIES 
15.1 
SMRP and Osteopontin Levels 
Patients who receive all 4 cycles of pemetrexed with cisplatin or carboplatin and then are 
randomized to either the treatment or observation arm will have blood samples obtained at 3 
distinct times during the course of the study: Baseline, prior to cycle 3 (week 6), and at the time 
of progression. Procedures for collecting and shipping the specimens are detailed in Section 6.2. 


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Two specific studies will be carried out on the samples obtained.  The first will be to determine 
the circulating levels of osteopontin in plasma and SMRP in serum of patients prior to treatment 
and following therapy. The circulating levels of osteopontin and SMRP will be determined using 
commercially available ELISA kits (R and D Systems; Mesomark). These will be carried out in 
the laboratory of 
 (University of Minnesota) as his laboratory has 
previously carried out on the serum of lung cancer patients.   
15.2 
Tumor Tissue Expression of Thymidylate Synthase (TS) 
TS expression in tumor tissue will be assessed by semiquantitative immunohistochemistry (IHC) 
using commercially available monoclonal antibodies (TS (2D8.D11) from Santa Cruz 
Biotechnology, Inc.) and automated IHC instrumentation. Determination of TS overexpression 
will be performed on unstained tumor tissue sections that have been placed onto glass slides. 
The Alliance Biorepository at Ohio State will provide five slides containing unstained sections 
for each case, which will be evaluated for TS expression and IHC control reactions.  
Paraffin embedded tissue sections are cut at 4 microns, deparaffinized with xylene and hydrated 
through graded alcohols and then rinsed in distilled water. The BiogGenex Antigen Retrieval 
procedure is carried out in a steamer under pressure.  The tissues are rinsed with distilled water 
and are subsequently rinsed with PBS after each step. They are treated with Peroxide block, 
Power block, Aviden, Biotin and are incubated with the primary antibody specific for the antigen 
to be demonstrated for 30-60 minutes. Sections are then incubated with MultiLink antibody (a 
biotinylated anti-immunoglobulin in PBS ) and followed by incubation with the Label 
(Perioxidase-conjungated streptavidin ). The antibody complex is then made visible by addition 
of a chromogen substrate until adequate color development is seen. Slides are washed in water 
to stop the reaction, counterstained, dehydrated, cleared and mounted with an aqueous mountant. 
This procedure is performed using an automated staining protocol on the BioGenex I6000 
autostainer with Biogenex reagents. 
15.3 
Analysis of Genetic Variants in the TYMS, DPYD and MTHFR Genes 
DNA will be extracted from 10 mL of whole blood collected into an EDTA- anticoagulated 
vacutainer. This DNA will be used for the analysis of constitutional genetic variants in the 
TYMS, DPYD, and MTHFR genes. Real time PCR will be used to assess the genetic status of 
each study patient with respect to the markers mentioned as these have been shown to affect the 
efficacy of therapeutics targeting thymidylate synthase. 
15.4 
Volumetric Tumor Measurements 
In this study, in addition to CT response evaluation by modified RECIST criteria (15), novel 
methods of radiologic assessment for mesothelioma will be used. These include specialized 
assessments of CT scans developed by 
 (MSKCC) and 
 (U. of 
Chicago). At the University of Chicago, this involves semi-automated measurements of the 
pleural rind (26). At MSKCC, computerized modeling that extracts pleural disease from 
surrounding chest wall and mediastinal structures is used to subsequently allow calculations of 
tumor volume (18). Mesothelioma tumor volumes have been associated with outcomes in one 
surgical study (17). In order to facilitate these studies, contrast enhanced CT scans at baseline, 
and subsequent 6, 9, and 12-week intervals will be performed using 2.5 mm cuts. This CT data 
in digital format will be submitted to the Imaging Core Lab at Ohio State which will collate and 
make available for analysis to 
 
Response status, as determined by modified RECIST will be used as the overall response in this 
trial. However, the semi-automated methods and the changes in tumor volumetrics described 


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above will also be calculated and compared as an exploratory endpoint to the modified RECIST 
in terms of time to response, time to progression and reproducibility.  
16.0 ADVERSE EVENT REPORTING (AER) 
Investigators are required by federal regulations to report serious adverse events as defined below. 
Investigators are required to notify the Alliance Central Protocol Operations Program Office, the 
Study Chair, and their Institutional Review Board if a patient has a reportable serious adverse event. 
The CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
will be utilized for AE reporting. The CTEP Active Version of the CTCAE is identified and located 
on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate 
treatment areas should have access to a copy of the CTEP Active Version of CTCAE. 
All reactions determined to be reportable in an expedited manner must be reported using the NCI 
Adverse Event Expedited Reporting System (CTEP-AERS).  


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16.1 
CALGB 30901 Reporting Requirements 
CTEP-AERS Expedited Reporting Requirements for Adverse Events That Occur Within 
30 Days1 of the Last Dose of Treatment 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs  
Expedited 10 calendar day reports for: 


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• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.  
Footnote “1” above applies after this reporting period. 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
• 
Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 5 calendar days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
within 10 calendar days of the investigator learning of the event.  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
16.2 
Additional Instructions or Exclusions from CTEP-AERS Expedited Reporting 
Requirements for CALGB 30901: 
• 
Grade 3/4 myelosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. 
• 
Grade 3/4 diarrhea or mucositis and hospitalization resulting from such do not require 
CTEP-AERS, but should be submitted as part of study results. 
• 
Reporting of cases of secondary AML/MDS is to be done using the NCI/CTEP Secondary 
AML/MDS Report Form. New primary malignancies should be reported using study form 
C-1001. 
• 
CTEP-AERS reports are to be submitted electronically using CTEP-AERS http://eapps-
ctep.nci.nih.gov/ctepaers/.  
• 
The reporting of adverse events described above is in addition to and does not supplant the 
reporting of adverse events as part of the report of the results of the clinical trial, e.g., study 
summary forms or cooperative group data reporting forms. 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted.  


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17.0 REFERENCES 
 
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Update #06 
 
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