Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Rare Diseases

Small Cell Lung Carcinoma

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Small Cell Lung Cancer

Antineoplastic Agents

All Drugs and Chemicals

Lipid Regulating Agents

Carboplatin

Etoposide

Cisplatin

Etoposide phosphate

Pravastatin

Enzyme Inhibitors

Anticholesteremic Agents

Hypolipidemic Agents

Antimetabolites

Hydroxymethylglutaryl-CoA Reductase Inhibitors

Should be given according to local practice but suggested doses and schedules are provided in the protocol.

carboplatin

cisplatin

Day 1: given by IV, days 2 and 3 given by IV or oral. Dose should be given according to local practice but suggested doses and schedules are provided in the protocol.

etoposide phosphate

40mg daily oral tablet taken for a maximum of 2 years

pravastatin sodium

Michael J. Seckl, MD, PhD

RATIONALE: Drugs used in chemotherapy, such as etoposide, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pravastatin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by making tumor cells more sensitive to chemotherapy. It is not yet known whether etoposide and cisplatin or carboplatin are more effective with or without pravastatin in treating small cell lung cancer.

PURPOSE: This randomized phase III trial is studying etoposide and cisplatin or carboplatin to see how well they work when given as first-line chemotherapy together with pravastatin compared with first-line chemotherapy and a placebo in treating patients with small cell lung cancer.

OBJECTIVES:

Primary

* Compare the survival of patients with small cell lung cancer treated with etoposide phosphate in combination with cisplatin or carboplatin as first-line chemotherapy with vs without pravastatin.

Secondary

* Compare the progression-free survival of patients treated with these regimens.
* Compare the local progression-free survival (local control) of these patients.
* Compare the response rate in these patients.
* Compare the toxicity of these regimens in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to disease stage (limited stage vs extensive stage), ECOG performance status (0 or 1 vs 2 or 3), and participating site. Patients are randomized to 1 of 2 treatment arms.

All patients receive chemotherapy comprising cisplatin IV or carboplatin IV on day 1 and etoposide phosphate IV on days 1-3 or orally twice daily on days 2 and 3. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

* Arm I: Patients receive oral pravastatin daily beginning on day 1 of chemotherapy and continuing for up to 24 months.
* Arm II: Patients receive oral placebo daily beginning on day 1 of chemotherapy and continuing for up to 24 months.

Some patients may undergo blood and urine sample collection at baseline and periodically during and after study treatment. Samples are examined by genetic analysis, metabonomics and proteomics (to detect expression of RAS proteins, phospho-Erk, and other signals downstream of RAS), and cholesterol measurements.

After completion of study treatment, patients are followed every 2 months for 1 year and every 3 months thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

PROJECTED ACCRUAL: A total of 842 patients will be accrued for this study.

Etoposide and Cisplatin or Carboplatin as First-Line Chemotherapy With or Without Pravastatin in Treating Patients With Small Cell Lung Cancer

A Multicentre Phase III Randomized Double Blind Placebo Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Patients With Small Lung Cancer

University College, London

Symptoms and General Pathology

Blood and Lymph Conditions

Diseases and Abnormalities at or Before Birth

Recurrence

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Congenital Abnormalities

Leukemia, Myelomonocytic, Acute

Leukemia, Monocytic, Acute

Leukemia, Erythroblastic, Acute

Leukemia, Megakaryoblastic, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Acute Monoblastic Leukemia

Acute Myelomonocytic Leukemia

Acute Erythroid Leukemia

Di Guglielmo's Syndrome

Acute Megakaryoblastic Leukemia

Acute Myeloblastic Leukemia Without Maturation

Acute Myeloblastic Leukemia With Maturation

Chronic Myeloproliferative Disorders

Analgesics

Anti-Infective Agents

Antirheumatic Agents

Dermatologic Agents

Mitoxantrone

Cyclosporine

Cyclosporins

Immunosuppressive Agents

Immunologic Factors

Clotrimazole

Miconazole

Antifungal Agents

Calcineurin Inhibitors

Patients receive cyclosporine IV continuously on days 5-9. Patients also receive pravastatin sodium PO every 6 hours on days 1-10, etoposide IV continuously on days 5-9, and mitoxantrone hydrochloride IV continuously on days 5-9. Treatment repeats for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR/CRi may receive 2 additional courses in the absence of disease progression or unacceptable toxicity.

cyclosporine

mitoxantrone hydrochloride

etoposide

bone marrow aspiration

Roland Walter

This phase I/II trial studies the side effects and best dose of etoposide and mitoxantrone hydrochloride when given together with cyclosporine and pravastatin sodium and to see how well they work in treating patients with relapsed or refractory acute myeloid leukemia (AML). Cyclosporine may inhibit efflux of cancer drugs out of cancer cells and may thereby improve chemotherapy treatment for AML. Pravastatin sodium may stop the growth of cancer cells by blocking some of the nutrients needed for cell growth. Drugs used in chemotherapy, such as etoposide and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving cyclosporine together with pravastatin sodium, etoposide, and mitoxantrone hydrochloride may kill more cancer cells

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated doses of mitoxantrone (mitoxantrone hydrochloride) and etoposide in combination with pravastatin (pravastatin sodium) and cyclosporine.

SECONDARY OBJECTIVES:

I. Describe the complete remission (CR)/CR with incomplete peripheral blood count recovery (CRi) rate after up to 2 cycles of induction therapy.

II. Describe the disease-free survival of patients that achieve CR/CRi. III. Estimate the frequency and severity of regimen-associated toxicities, along with 28-day mortality after start of study treatment.

OUTLINE: This is a phase I/II, dose-escalation study of etoposide and mitoxantrone hydrochloride in combination with pravastatin sodium and cyclosporine.

Patients receive cyclosporine intravenously (IV) continuously on days 5-9. Patients also receive pravastatin sodium orally (PO) every 6 hours on days 1-10, etoposide IV continuously on days 5-9, and mitoxantrone hydrochloride IV continuously on days 5-9. Treatment repeats for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR/CRi may receive 2 additional courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 month.

Cyclosporine, Pravastatin Sodium, Etoposide, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Cyclosporine Modulation of Drug Resistance in Combination With Pravastatin, Mitoxantrone, and Etoposide for Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML): A Phase 1/2 Study

Determine the doses of mitoxantrone and etoposide that, when combined with CSA and pravastatin, meet minimum standards for both efficacy and toxicity and have the highest efficacy rate among several mitoxantrone and etoposide doses.

Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Describe the disease-free survival of patients that achieve Complete Remission (CR)/CR with inadequate recovery of peripheral blood cell counts (CRi).

Categorized according to criteria recommended by an International Working Group.

Describe the disease-free survival of patients that achieve CR/CRi.

Estimate the frequency and severity of regimen-associated toxicities, along with 28-day mortality after start of study treatment

National Cancer Institute (NCI)

Fred Hutchinson Cancer Center

Principal Investigator

Patients receive cyclosporine IV continuously on days 5-9. Patients also receive pravastatin sodium PO every 6 hours on days 1-10, etoposide IV continuously on days 5-9, and mitoxantrone hydrochloride IV continuously on days 5-9. Treatment repeats for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR/CRi may receive 2 additional courses in the absence of disease progression or unacceptable toxicity.

cyclosporine: Given IV

pravastatin sodium: Given PO

mitoxantrone hydrochloride: Given IV

etoposide: Given IV

bone marrow aspiration: Correlative studies

Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)

Age, Continuous

Sex: Female, Male

Roland B. Walter, MD, PhD, MS

Maximum Tolerated Doses Mitoxantrone Hydrochloride and Etoposide When Combined With Cyclosporine and Pravastatin Sodium

CR/CRi

Disease-free Survival of Patients That Achieve CR/CRi

Frequency and Severity of Regimen-associated Toxicities

Overall Study

Cytarabine

Idarubicin

Antiviral Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Induction (1 cycle):

pravastatin 1280 mg/d PO D 1-8 idarubicin 12 mg/m2/d IV D 4-6 cytarabine 1.5 g/m2/d continuous IV D 4-7

Consolidation (up to 2 cycles):

pravastatin 1280 mg/d PO D 1-6 idarubicin 12 mg/m2/d IV D 4-5 cytarabine 1.5 g/m2/d continuous IV D 4-5

1.5 g/m2/day given by continuous IV on days 4-7

cytarabine

12 mg/m2/day given intravenously over 10-15 minutes on days 4-6

idarubicin

Anjali Advani, MD

RATIONALE: Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Pravastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Pravastatin may also help idarubicin and cytarabine work better by making cancer cells more sensitive to the drugs. Giving idarubicin and cytarabine together with pravastatin may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving idarubicin and cytarabine together with pravastatin works in treating patients with relapsed acute myeloid leukemia (AML).

ADDITIONAL BACKGROUND: S0919 was initially designed for patients with relapsed acute myeloid leukemia (AML), where the patient's preceding remission had lasted ≥ 3 months. The null response rate was 30%. The study closed to accrual on Nov 1, 2012 after meeting the defined criterion for a positive study; and the results are being submitted to the American Society of Clinical Oncology meeting. Based on the promising results from this trial, the trial has now been amended to evaluate this therapeutic regimen in poor-risk patients (patients with newly diagnosed acute myeloid leukemia (AML) arising out of myelodysplastic syndrome (MDS), primary refractory acute myeloid leukemia (AML), and relapsed acute myeloid leukemia (AML) with the patient's preceding remission lasting \< 6 months).

COHORTS:

Cohort 1 (Initial cohort: Relapsed AML with previous remission ≥ 3 months), Cohort 2 (Poor-risk cohort: MDS transformed to AML), Cohort 3 (Poor-risk cohort: Refractory or relapsed AML with previous remission \< 6 months)

OBJECTIVES:

* To test whether the complete remission (CR) rate (including CR with incomplete recovery) in patients with relapsed acute myeloid leukemia (AML) treated with idarubicin and cytarabine in combination with pravastatin is sufficiently high to warrant a phase III investigation.
* To estimate relapse-free survival and overall survival rates in these patients.
* To estimate the frequency and severity of toxicities of this regimen in these patients.
* To evaluate, in a preliminary manner, whether pre-study cytogenetic features correlate with response in these patients.

OUTLINE: This is a multicenter study.

* Induction therapy: Patients receive oral pravastatin once daily on days 1-8, idarubicin IV over 10-15 minutes on days 4-6, and cytarabine IV continuously on days 4-7. Patients achieving complete remission proceed to consolidation therapy.
* Consolidation therapy: Beginning 30-60 days after the start of induction therapy, patients receive oral pravastatin once daily on days 1-6 and idarubicin IV over 10-15 minutes and cytarabine IV continuously on days 4 and 5. Treatment repeats approximately every 5 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for 5 years.

S0919 Idarubicin, Cytarabine, and Pravastatin in Treating Patients With Relapsed Acute Myeloid Leukemia

S0919, A Phase II Study of Idarubicin and Ara-C in Combination With Pravastatin for Poor-Risk Acute Myelogenous Leukemia

OS is calculated for all participants from the date of initial registration on study until death from any cause. Observations for participants last known to be alive were censored.

RFS is calculated for participants who have achieved a complete response (CR) or CR with incomplete blood count recovery (CRi). RFS will be measured from the date of CR or CRi until relapse from CR or CRi for death from any cause. Observation is censored at the date of last follow-up for patients last known to be alive without report of relapse.

Per the Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia, morphologic complete remission requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of ≥ 100,000/μL.

Participants who achieved morphological complete remission with or without incomplete blood count recovery.

Per the Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia, morphologic complete remission requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of ≥ 100,000/μL.

Number of patients with Grade 3-5 adverse events that were possibly, probably or definitely related to study drug are reported by given type of adverse event

SWOG Cancer Research Network

Adverse Events (AEs) are reported by CTCAE Version 4.0. All adverse events, regardless of attribution or grade, are reported for patients who received study treatment. 1 patient in the initial cohort was taken off protocol therapy before AEs were assessed.

Participants with previous morphologically confirmed acute myeloid leukemia (AML), and preceding remission lasting ≥ 3 months

Initial Cohort: Relapsed AML With Previous Remission ≥ 3 Mnths

Participants with acute myeloid leukemia (AML) who had a previous morphologically confirmed diagnosis of MDS/CMML and for which they may have received previous non-intensive therapy.

Poor-risk Cohort: MDS Transformed to AML

Participants with previous morphologically confirmed acute myeloid leukemia (AML), and preceding remission lasting \< 6 months.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Etoposide and Cisplatin or Carboplatin as First-Line Chemotherapy With or Without Pravastatin in Treating Patients With Small Cell Lung Cancer	NCT00433498	Lung Cancer	carboplatin cisplatin etoposide phosp... pravastatin sod...	18 Years -	University College, London
Etoposide and Cisplatin or Carboplatin as First-Line Chemotherapy With or Without Pravastatin in Treating Patients With Small Cell Lung Cancer	NCT00433498	Lung Cancer	carboplatin cisplatin etoposide phosp... pravastatin sod...	18 Years -	University College, London
Cyclosporine, Pravastatin Sodium, Etoposide, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia	NCT01342887	Adult Acute Meg... Adult Acute Min... Adult Acute Mon... Adult Acute Mon... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Erythrole... Adult Pure Eryt... Recurrent Adult...	cyclosporine pravastatin sod... mitoxantrone hy... etoposide bone marrow asp...	18 Years -	Fred Hutchinson Cancer Center
S0919 Idarubicin, Cytarabine, and Pravastatin in Treating Patients With Relapsed Acute Myeloid Leukemia	NCT00840177	Leukemia	cytarabine idarubicin pravastatin sod...	18 Years -	SWOG Cancer Research Network

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