Know Cancer

forgot password

Adjuvant Chemotherapy With Pemetrexed and Cisplatin vs. Vinorelbine and Cisplatin in NSCLC IB, IIA, IIB, T3N1: a Randomized Phase II Study

Phase 2
18 Years
74 Years
Open (Enrolling)
Non-small Cell Lung Cancer

Thank you

Trial Information

Adjuvant Chemotherapy With Pemetrexed and Cisplatin vs. Vinorelbine and Cisplatin in NSCLC IB, IIA, IIB, T3N1: a Randomized Phase II Study

Derived from recent large randomized clinical trials, there is clear evidence for adjuvant
chemotherapy in stage IB-IIB (incidental IIIA) non-small cell lung cancer (Arriagada et al.,
2004; Winton et al., 2005, Strauss et al., 2004, Douillard et al., 2005). The majority of
patients in the adjuvant treatment setting received a combination of Cisplatin and
Vinorelbine (Aragiada et al., 2004; Winton et al., 2005; Douillard et al., 2005). This
combination improved 5 year-survival rates up to 15% (54% to 69%) (Winton et al., 2005).
However, the combination of Cisplatin and Vinorelbine resulted in rates of grade 3/4
neutropenia of around 75%, rates of febrile neutropenia of up to 12.5% and rates of
treatment related death of 1-2%. Up to 77% of the patients had at least one dose reduction
or omission and 55% required one dose delay or more, most related to neutropenia. Only about
50 % of patients randomized on the combination of cisplatin and vinorelbine received the
intended dose of Vinorelbine (dose reduction mainly due to toxicity) and only 50% of
patients completed all four cycles of chemotherapy (Winton et al., 2005, Douillard et al.,
2005, Alam et al., 2005).

Therefore it seems reasonable to test a less toxic regimen also in early stages after R0
resection of the tumor, where reduced toxicities might improve the feasibility of drug
delivery, compliance and the convenience of treatment for the patient and hence perhaps

Pemetrexed, a folate antimetabolite, shows clear activity in non-small cell lung cancer with
several Phase II studies of Pemetrexed in combination with Cisplatin, Oxaliplatin, or
Carboplatin showing efficacy similar to other standard platinum doublets, with response
rates of 27% to 45% and median survival of 8.9 to 10.9 months (Scagliotti et al., 2005;
Clarke et al., 2002; Rusthoven et al., 1999; Manegold et al., 2000; Shepherd et al., 2001).
The combination of platin and Pemetrexed can be easily delivered and is well tolerated.
Furthermore, it only results in a 25% rate of grade 3/4 neutropenia and in vitamin
supplemented patients the incidence of febrile neutropenia was < 1%. Dose reductions occur
only in 2-4% of the patients and dose delivery of the intended Pemetrexed and platin dose is
excellent with dose deliveries of Pemetrexed up to 95% (Hanna et al., 2004; Vogelzang et
al., 2003, Scagliotti et al., 2005).

In this randomized phase II trial, the clinical feasibility of the combination of Cisplatin
and Pemetrexed as well as of the combination of Cisplatin and Vinorelbine will be assessed.
Treatment is considered to have clinical feasibility if dose limiting toxicity will not be
observed, and no non-acceptance by the patient leading to premature withdrawal, and no death
due to cancer or cancer therapy will occur.

Patients will be randomized according to center, lobectomy vs. pneumonectomy and N0 vs. N1
to 4 cycles (arm A) of 500 mg/m2 pemetrexed d1, and Cisplatin 75 mg/m2 d1, q d22 versus (arm
B) 25 mg/m2 Vinorelbine d1, 8, 15, 22, and Cisplatin 50 mg/m2 d1+8; q d29. Radiotherapy or
maintenance therapy are not intended. Study drug administration will begin on d28 to d42
after R0 resection of the tumor and within 14 days after randomization.

In an initial study phase 36 patients (i.e. 18 in each treatment arm) will be accrued to
confirm feasibility. In the second step, further patients will be recruited up to a total
number of 134 (i.e. 67 cases per treatment arm). Patients will be followed-up in 3 monthly
intervals for the first 2 years starting 30 days after end of the last cycle and in the 3rd
year patients will be followed-up in 6 monthly intervals.

Inclusion Criteria

Inclusion criteria:

- Histopathologically confirmed diagnosis of non-small cell lung cancer (NSCLC),
pathologic stage IB, IIA, IIB or T3N1 (without need for further radiotherapy).

- Complete tumor resection without detectable residual tumor including negative margins
(R0) and systematic intraoperative dissection of mediastinal lymph nodes of course
lymph node dissection has to comprise all lymph node levels to be removed with
standard right or left sided resection. The dissection has to assure the removal of
mediastinal lymph nodes more than 1,5 cm on the preoperative CT scan.

- Study drug administration should only be administered to patients with full recovery
after surgery and is to begin on d28 to d42 postoperatively

- The following histological tumor types are eligible:

- Squamous Cell Carcinoma

- Adenocarcinoma (including adenocarcinomas with bronchioloalveolar differentiation)

- Large Cell Carcinoma (excluding tumors with slight areas of small cell carcinoma)

- Mixed Cell Carcinoma without small cell fraction

- Provision of informed consent according to local regulatory requirements for
participation in the study

- Age ≥ 18 years; < 75 Years

- Karnofsky Performance Status 80% or ECOG 1

- Adequate hematological laboratory parameters

- Hemoglobin 10 g/dl

- ANC 1500/µl

- Platelets 100000/µl

- Adequate hepatic laboratory parameters

- Bilirubin 1.5 x UNL (UNL=Upper Normal Limit )


- Adequate renal laboratory parameters

- Creatinine 1,5 mg/dl and

- Calculated Creatinine Clearance 60 ml/min

- Cardiac function allowing cisplatin chemotherapy (in case of doubt echocardiography
is mandatory documenting LVEF >49%)

- Electrocardiogram without significant cardiac arrhythmia

- FEV1 1.2 l post-operatively

- Respiratory function not impeding Cisplatin-based chemotherapy assessed by either
absolute DLCO or capillary / arterial BGA in resting condition (absolute DLCO > 40 %
or pO2 >60 mmHg in resting condition)

- Agreement by the patient to use an effective method of contraception

- Negative pregnancy test for women of childbearing potential unless they are
postmenopausal at baseline. (Postmenopausal women must have been amenorrheic at least
for 12 months to be considered of non childbearing potential)

Exclusion criteria:

- Presence of a Pancoast tumor

- Involvement of N2/N3 lymph nodes

- Distant metastases

- The following histological tumor types are excluded

- Pure bronchioloalveolar carcinoma

- Mixed cell carcinoma with small cell fractions

- Large Cell Carcinoma with areas of small cell carcinoma

- Pregnancy or lactation period

- Other co-existing malignancies or malignancies diagnosed within the last 5 years with
the exception of a CIS of the cervix or non-melanomatous skin cancer. Patients
curatively treated and free of disease for at least 5 years will be discussed with
the Principal Investigator (LKP) before inclusion.

- Radio- and/or chemotherapy within the last five years

- Concurrent administration of any other antitumor therapy

- Patients who are not compliant with vitamin (folic acid and vitamin B12) intake or to
whom administration is not possible

- Hypersensitivity to Pemetrexed or to any of the excipients of Alimta®

- Hypersensitivity to Cisplatin or to any other platinum compound

- Hypersensitivity to Vinorelbin or to any other vinca-alkaloid

- Patient has previously completed or withdrawn from this study or any other study with
the respective medication in this study

- Treatment with an investigational new drug, currently or within the last 30 days,
and/or participation in another clinical trial, currently or during the last 12
weeks, and/or previous participation in this study

- History of a psychological illness or condition such as to interfere with the patient
s ability to understand the requirements of the study

- Patients with any clinically significant disease that in the opinion of the
investigator is likely to put the patient at risk or to interfere with the evaluation
of the patient's safety and of the study outcome. This includes, but is not limited

- Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic
coronary artery disease and cardiac arrhythmia not well controlled with medication)
or myocardial infarction within the last 6 months

- Uncontrolled hypertension

- Interstitial pneumonia or extensive or symptomatic interstitial fibrosis of the lung

- pleural effusion or ascites, which cause respiratory compromise. Patients with
sero(pneumo)-thorax after hemi-pneumonectomy or lobectomy will not be excluded. Those
patients must be monitored for toxicity closely

- Any other active or uncontrolled infection

- Organ allografts

- Patients with neurologic disorders

- A history or presence of any CNS disorder or psychiatric disability judged by the
Investigator to be clinically significant and/or interfering with compliance

- A serious concomitant systemic disorder (e.g. active infection including HIV) that in
the opinion of the investigator would compromise the patient s ability to complete
the study

- Post-operative complications or other surgery-related conditions that could interfere
with a study participation

- Hearing function / tinnitus impeding chemotherapy with Cisplatin and / or Vinorelbine

- Alcohol and/or drug abuse

- Patient is unable to interrupt high dose salicylates (like aspirin) or other
non-steroidal anti-inflammatory drugs (NSAID´s) for a 5-day period starting 2 days
before administration of Pemetrexed (8-day period for long-acting agents such as

- Patients who cannot be regularly observed for psychological, sociological or
geographical reasons or other concomitant conditions not permitting adequate
follow-up and compliance to the protocol

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the clinical feasibility rate of 4 cycles of adjuvant chemotherapy with Pemetrexed and Cisplatin vs. Vinorelbine and Cisplatin

Outcome Time Frame:

4 month

Safety Issue:


Principal Investigator

Michael Thomas, Prof. Dr.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Clinic for thoracic diseases at the University of Heidelberg, Germany


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

October 2006

Completion Date:

December 2013

Related Keywords:

  • Non-Small Cell Lung Cancer
  • Non-small cell lung cancer
  • adjuvant therapy
  • clinical feasibility rate
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms