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GSK - Doublet: A Phase I Study of Pegylated Liposomal Doxorubicin (Doxil) and Weekly Intravenous Topotecan in Patients With Advanced Solid Tumors

Phase 1
18 Years
Not Enrolling
Small Cell Lung Cancer, Pancreatic Cancer, Head and Neck Cancer, Gastric Cancer, Esophageal Cancer

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Trial Information

GSK - Doublet: A Phase I Study of Pegylated Liposomal Doxorubicin (Doxil) and Weekly Intravenous Topotecan in Patients With Advanced Solid Tumors

Topotecan is a semisynthetic analogue of camptothecin. Like its parent compound
camptothecin, topotecan is a specific inhibitor of topoisomerase-I. Topoisomerase-I
facilitates DNA replication by inducing reversible single strand breaks thereby relieving
the torsional strain which occurs ahead of the moving replication fork during DNA
replication. Topotecan binds to the topoisomerase-I DNA complex and prevents relegation of
the single strand breaks resulting in double strand DNA breaks. The cytotoxic action of
topotecan is proportional to the cellular level of topoisomerase-I.

Doxorubicin is an anthracycline antibiotic which has a wide range of clinical activities.
The mechanism of cytotoxicity and the exact intracellular target remains controversial. The
bulk of intracellular drug is intranuclear much of which is intercalated in the DNA.
Although DNA intercalation has been felt to be the principle cytotoxic mechanism, more
recent evidence suggests inhibition of topoisomerase-II may play a more important role.
Additionally, other cytotoxic actions including helicase inhibition have recently been
noted. Pegylated liposomal doxorubicin (Doxil) is a polyethylene glycol pegylated liposomal
encapsulation of doxorubicin. This results in an alteration of the pharmacokinetics in
comparison to the parent compound. Specifically there is a prolonged circulation time,
reduced clearance, a smaller volume of distribution, and limited uptake by the
reticuloendothelial system. In animals using ovarian xenografts in nude mice, pegylated
liposomal doxorubicin has resulted in a greater tumor to normal tissue drug uptake and an
improved therapeutic index. Following phase I studies, Doxil has recently been studied in a
phase II study of heavily pre-treated ovarian carcinoma patients with a response rate of
25.7%. This level of activity meets or exceeds other second-line agents currently available.
In the recent phase II study, a dose of 50 mg/m2 every 3 weeks was utilized.

Topotecan given as 5 daily infusions is associated with significant myelosuppression and
poor patient acceptance. Non hematologic toxicities are usually mild and not dose-limiting.
Although the 5 day schedule can be inconvenient, the relative lack of acute toxicity still
makes topotecan a good candidate for out-patient chemotherapy in selected patients.
Although the impact of bone marrow suppression can be minimized by the use of cytokines,
these 5 day regimens have required substantial dose reduction.

In view of the bone marrow toxicity seen with topotecan and the poor patient acceptance of a
five day schedule, there has been interest in the development of an effective alternate
treatment regimen using topotecan. Results from preclinical studies suggest that repeated
administration of topotecan is necessary for its activity. A phase I study evaluating the
safety and efficacy of weekly bolus topotecan as a second line agent in relapsed ovarian
cancer resulted in a maximum tolerated dose of 5 mg/m2.

A phase II study in relapsed ovarian cancer supports the use of weekly topotecan at a dose
of 3 - 4.0 mg/m2/week. Toxicities on this weekly regime have included, grade 3 or 4
neutropenia, anemia, thrombocytopenia, fatigue and GI toxicity, each occurred following less
than 1% of treatments.

The combination of topoisomerase-I and topoisomerase-II inhibitors is an attractive strategy
for cancer chemotherapy. A phase II study evaluated the combination of pegylated liposomal
doxorubicin 30mg/m2/week with topotecan 1 mg/m2 IV for 5 consecutive days given every 28
days. Twelve patients with platinum resistant ovarian cancer were treated. Partial
response was observed in three patients and four patients had stable disease of the ten
patients evaluated for response. Toxicities included a higher percentage of bone marrow
toxicity (grade III/IV neutropenia, grade III/IV thrombocytopenia) other toxicities included
alopecia and diarrhea grade II/III. The authors concluded that the combination of topotecan
and pegylated liposomal doxorubicin is active in the treatment of platinum resistant ovarian
cancer. However, myelosuppression required dose reductions in nearly half the patients.

As mentioned earlier, a weekly regimen of topotecan has allowed for more convenient
administration over more prolonged and more complex administration schedules. The current
study will evaluate the tolerability of a weekly intravenous schedule of topotecan in
combination with a standard dose of pegylated liposomal doxorubicin in advanced solid
tumors. Due to the addition of the pegylated liposomal doxorubicin to a weekly schedule of
topotecan, Pharmacokinetics data will also be obtained.

Inclusion Criteria:

- ECOG functional status of 2 or better is required.

- The patient should be able to provide informed consent.

- Prior treatment with Doxil or topotecan is not permitted.

- Prior treatment with doxorubicin is permitted if the total dose was 350 mg/m2 or
less. Prior treatment with epirubicin is permitted if the total dose was 560 mg/m2.

- Patients with controlled brain metastases will be considered eligible for therapy
(i.e. metastases surgically removed; or irradiated metastases with stable neurologic

- Patients must have measurable disease (the presence of at least one measurable

- If previously irradiated lesions are to be used to measure response, documented
growth of the lesions must have been observed following completion of radiation

- Patients must have a life expectancy of at least four weeks.

- Hematologic criteria: patients must have absolute neutrophil count (ANC) of 1200 or
better; platelet count of 100,000/mm3 or better; hemoglobin (Hgb) ≥ 9.0g/dL.

- Hepatic criteria: bilirubin must be less than or equal to 1.7. SGOT, SGPT may be up
to 2 x institutional upper limit of normal (ULN) but with the presence of liver
metastasis the SGOT, SGPT may be up to 3 x institutional ULN.

- Serum creatinine must be < 1.5 mg/dl x ULN

- Patients with reproductive potential must use an adequate contraceptive method (e.g.,
abstinence, intrauterine device, oral contraceptives, barrier device with spermicide
or surgical sterilization) during treatment and for three months after completing

- Patients must have a multigated acquisition (MUGA) scan or 2-d echocardiogram
indicating an ejection fraction of ≥ 50% within 42 days prior to first dose of study
drug. The method used at baseline must be used for later monitoring.

Exclusion Criteria:

- Patients with concurrent severe medical problems unrelated to malignancy, which would
limit full compliance to the study or expose the patient to extreme risk with
decreased life expectancy, are ineligible.

- Patients with previous or concomitant malignancy other than curatively treated
carcinoma in situ of the cervix, basal cell or squamous cell carcinoma of the skin,
or other primary cancer completely resected or treated within five years are
ineligible. Exceptions are patients who have had tumors treated with no evidence of
active disease who are felt by both the enrolling physician and the principal
investigator (PI) to have a risk of relapse of less than 30%.

- Pregnant or lactating women.

- History of hypersensitivity reactions attributed to a conventional formulation of
doxorubicin hydrochloride (HCL) or the components of Doxil®.

- History of cardiac disease with New York Heart Association Class III or greater, or
clinical evidence of congestive heart failure.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Parameters of response: tumor measurement: Response Evaluation Criteria in Solid Tumors (RECIST) criteria

Outcome Time Frame:

every other cycle

Safety Issue:


Principal Investigator

Michael J. Guarino, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Christiana Care Health Services


United States: Institutional Review Board

Study ID:




Start Date:

May 2004

Completion Date:

June 2008

Related Keywords:

  • Small Cell Lung Cancer
  • Pancreatic Cancer
  • Head and Neck Cancer
  • Gastric Cancer
  • Esophageal Cancer
  • Metastatic cancer
  • Metastatic gastric and esophagus adenocarcinoma
  • Unresectable pancreatic cancer
  • Unresectable head and neck cancer
  • Cancer of undetermined primary
  • Esophageal Diseases
  • Esophageal Neoplasms
  • Head and Neck Neoplasms
  • Lung Neoplasms
  • Stomach Neoplasms
  • Pancreatic Neoplasms
  • Small Cell Lung Carcinoma



Christiana Care Health ServicesNewark, Delaware  19713