Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Analgesics

Etoposide

Cytarabine

Mitoxantrone

Molgramostim

Sargramostim

Daunorubicin

Etoposide phosphate

Enzyme Inhibitors

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

* Daunorubicine (CérubidineR) : 80 mg/m2/jour IV over 30 min from day 1 to day 3,
* AraC (AracytineR) : 500 mg/m2/jour IV from day 1 to day 3,
* Mitoxantrone (NovantroneR) : 12 mg/m2/jour IV over 30 min from day 8 to 9
* AraC (AracytineR) : 500 mg/m2/12h IV over 3 hours from day 8 to day10.
* GM-CSF (LeucomaxR): 5 µg/kg/jour IV over 6 hours from day 1 to day 10.

* Daunorubicine (CérubidineR) : 80 mg/m2/jour IV over 30 min from day 1 to day 3,
* AraC (AracytineR) : 500 mg/m2/jour IV from day 1 to day 3,
* Mitoxantrone (NovantroneR) : 12 mg/m2/jour IV over 30 min from day 8 to 9
* AraC (AracytineR) : 500 mg/m2/12h IV over 3 hours from day 8 to day10.

* AraC (Aracytine) : 3 g/m2/12h IV (3 hours) on days 1, 3 , 5
* GM-CSF :5 µg/kg/d IV (6 hours) from day1 to day 5

- AraC (Aracytine) : 3 g/m2/12h IV (3 hours) on days 1, 3 , 5

Randomization 1: GM-CSF (5micogram/Kg/d) versus no GM-CSF during induction chemotherapy and all consolidation courses.

Randomiization 2: Consolidation high dose AraC versus consolidation EMA

GM-CSF

XAVIER THOMAS, MD, PhD

The purpose of this study is:

1. To compare priming with Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) during induction and consolidation courses versus no priming.
2. To compare as consolidation timed sequential chemotherapy versus four courses of high dose cytarabine.

Patients aged 15-50 are enrolled and randomly assigned to receive GM-CSF or no GM-CSF during all remission-induction and consolidation courses of chemotherapy. Induction chemotherapy consists of a timed-sequential chemotherapy including a first sequence of chemotherapy combining daunorubicin, 80 mg/m2 per day, administered IV as a short infusion over 3 days (days 1-3), and cytarabine, 500 mg/m2 per day IV as a continuous infusion over the same period. The second sequence, administered after 4-day free interval, consists of mitoxantrone, 12 mg/m2 per day, administered IV as a short infusion over 2 days (days 8 and 9), and cytarabine, 500 mg/m2/12h, administered as a 3-hour infusion for 3 days (days 8-10). Salvage therapy consists of cytarabine, 3 g/m2/12h on days 1,3,5,7, combined with amsacrine, 100mg/m2 per day on days 1 to 3. GM-CSF (Leucomax, recombinant human GM-CSF from Escherichia Coli, Schering Plough, Kenilworth,N.J., USA) is given at a dose of 5µg/kg per day, intravenously beginning at day 1 of each chemotherapy course and continuing until the last day of chemotherapy of each course.

Patients who achieve CR after induction chemotherapy or salvage therapy are randomly assigned to consolidation courses consisting of either a timed sequential chemotherapy similar to that of the ALFA-9000 trial (P2 arm) or the CALGB postremission chemotherapy (P1 arm), which includes 4 cycles of high-dose cytarabine, followed by 4 additional maintenance courses.

Effect of Priming During Induction and Consolidations in Younger Acute Myeloid Leukemia (AML)

Effect of Priming With Granulocyte-Macrophage Colony-Stimulating Factor During Chemotherapy and Comparison of Timed Sequential Chemotherapy vs 4 Courses of High Dose Cytarabine as Consolidation in Younger Adults With Newly Diagnosed AML

Hospices Civils de Lyon

Acute Leukemia French Association

Xavier THOMAS, MD, PhD

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Reproductive Control Agents

Estrogens, Conjugated (USP)

Estrogens

Ethinyl Estradiol

Estradiol 17 beta-cypionate

Estradiol 3-benzoate

Estradiol

Polyestradiol phosphate

Hormones

Hormone Antagonists

Contraceptive Agents

Contraceptive Agents, Hormonal

Contraceptive Agents, Female

Contraceptives, Oral

Contraceptives, Oral, Hormonal

Tab Premarin 0.625 mg (Ethinyl estradiol) once a day for 5 days prior to each cycle of chemotherapy

Tab Placebo once a day for 5 days prior to each cycle of chemotherapy

Tab Premarin (Ethinyl estradiol)

Placebo once a day for 5 days prior to each cycle of chemotherapy

Placebo

Sudeep Gupta, MD, DM

One of the basic principles of cancer chemotherapy is that these drugs act exclusively or mainly on cells in cycle. Estrogens have been shown to increase the fraction of breast cancer cells in cycle. Tamoxifen on the other hand, decreases the proliferative fraction and has been shown to negatively impact on the results of adjuvant chemotherapy in breast cancer when given concomitantly. A number of previous studies have attempted estrogenic recruitment of cancer cells (into cell cycle) to increase the efficacy of chemotherapy in locally advanced and metastatic breast cancer. Although some studies showed an increase in response rates in the recruitment arm, there was no benefit in time to progression or survival in any of the studies. These results may have been due to the inadequate sample size of the studies and advanced stage disease (with presumably higher fraction of inherently chemoresistant cells). The present study is designed to test the hypothesis that estrogenic recruitment of micrometastatic disease in operable breast cancer will increase the efficacy of standard adjuvant chemotherapy after surgery. The intervention arm of the study will involve administration of short duration estrogen prior to each cycle of adjuvant chemotherapy. The end-points are disease free and overall survival.

Results from a recent clinical study (1) show that tamoxifen administered concurrently with chemotherapy reduces the efficacy of the latter in patients with estrogen and/or progesterone receptor positive breast cancer. Tamoxifen exerts its anti-tumour efficacy in breast cancer primarily by its anti-estrogenic effect on the breast tissue. Anti-estrogenic effects of tamoxifen are mediated by competitive inhibition of the estrogen receptor, resulting in reduced transcription of estrogen-regulated genes (2). This results in blockade of cell cycle transit in G1 phase and inhibition of tumour growth. This mechanism of action might be the theoretical basis of the negative effect of concomitantly administered tamoxifen on the efficacy of adjuvant chemotherapy and could be explained thus: Most human solid tumours grow (and regress) following Gompertzian kinetics rather than the exponential one (3). The fundamental difference between Gompertzian and exponential models is that the growth fraction of the tumour (the fraction of cells in cell cycle) decreases with tumour growth in the former whereas in the latter it remains constant. Since many chemotherapeutic agents cause cell kill only in the fraction that is in cell cycle, this is used to explain (partly) the failure of chemotherapy in large tumours. Since tamoxifen also causes cell cycle arrest (in G1) and decreases the growth fraction, it could also impair the effects of chemotherapy in an analogous fashion. This is the result seen in this randomized trial.

The fraction of cells in cycle in breast cancer is low (5 to 10%) as determined by thymidine labeling index (4). Since most chemotherapeutic agents act preferentially or exclusively on cycling tumor cells, it is theoretically and intuitively appealing to increase the fraction of cycling cells to enhance the efficacy of chemotherapy. One way to do it in breast cancer would be to administer estrogen, which is known to enhance the proliferation of breast cancer cells. Weichselbaum et al (5) demonstrated that low concentrations of estradiol (10-9 M) increased the fraction of cells in S-phase and enhanced the rate of cell proliferation in estrogen receptor positive MCF-7 breast cancer cell line. The cell kill of this cell line on exposure to cytosine arabinoside was enhanced. Others have shown that even estrogen receptor negative tumors have increased cell proliferation in response to estrogenic stimuli (6). This has been explained partly as a result of modulation of the kinetic response of cancer cells to other growth factors (7,8). There have been a number of randomized studies in literature to test the concept of kinetic recruitment of breast cancer cells by estrogens to increase the efficacy of chemotherapy (9-14). All these studies have used diethylstilbesterol (DES) for few days before standard chemotherapy for breast cancer to recruit cells into cycle and all these studies have been in patients with locally advanced (LABC) or metastatic breast cancer (MBC). The results of these studies have largely been negative. In the trial by Baldine et al (14) in LABC patients there was no difference in the response rates between DES-CAF and CAF arms (56% Vs 63%) and no difference in the overall (47 Vs 49 months) and progression free (21 Vs 24 months) survival. DES-CAF was found to be more myelotoxic compared to CAF alone, which resulted in reduced dose intensity in the former. In the trial by Conte et al (13) patients of MBC were randomized to DES-CEF versus CEF alone. Again, there was no difference in the response rages (49% Vs 57%) and overall survival (20 Vs 17 months) in between DES-CEF and CEF, the former being more myelotoxic. In the trial by Ingle et al (12) in MBC patients, the response to DES-CMF was higher (39% Vs 25%, p=0.06) compared to CMF alone but there was no difference in time to disease progression or survival. In the study by Paridaens et al (11) in LABC and MBC patients, ethinyl-estradiol plus CAF was compared to CAF. There was no difference in response rates, time to progression or survival in the two groups. Toxicities were also similar.

To summarize, the results of estrogenic recruitment in patients with LABC or MBC have been negative with respect to survival but some studies have shown a trend towards higher response rates in the recruitment arm. There are two possible explanations for these negative results. All these studies have been in metastatic or locally advance breast cancer patients. It is possible that the fraction of cells with inherent chemoresistance is higher in these patients compared to early stage patients and this would negate any beneficial effect of cell recruitment into cycle. Secondly, the total trial size has been small (less than 260) in all these studies and therefore they were grossly underpowered to detect meaningful differences between the two groups.

As a direct corollary of the negative effect of tamoxifen administered concomitantly with chemotherapy and the proven ability of estrogens to increase the proliferating fraction in breast cancer cells, we hypothesize a beneficial effect of estrogen priming on the efficacy of standard adjuvant chemotherapy in operable breast cancer. Since the effect is hypothesized on micrometastasis, it is likely that chemoresistance will be a lesser or no impediment.

Thus in a manner that is inverse to tamoxifen, estradiol could 'prime' the tumour for subsequent chemotherapy. Since only operable breast cancer patients who have undergone surgery and need adjuvant chemotherapy will be the test population, the estradiol priming will theoretically act on micrometastases that chemotherapy seeks to eradicate.

Estrogen Priming to Increase the Efficacy of Adjuvant Chemotherapy in Operable Breast Cancer

Estrogen Priming to Increase the Efficacy of Standard Adjuvant Chemotherapy in Operable Breast Cancer.

Duration in months between Date of randomization and date of first disease progression

Duration in months between Date of randomization and date of death by any cause disease progression

Sudeep Gupta

Professor of medical oncology

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effect of Priming During Induction and Consolidations in Younger Acute Myeloid Leukemia (AML)	NCT00880243	Acute Myeloid L...	GM-CSF	15 Years - 50 Years	Acute Leukemia French Association
Estrogen Priming to Increase the Efficacy of Adjuvant Chemotherapy in Operable Breast Cancer	NCT00193726	Breast Cancer	Tab Premarin (E... Placebo	18 Years - 70 Years	Tata Memorial Hospital
Effect of Priming During Induction and Consolidations in Younger Acute Myeloid Leukemia (AML)	NCT00880243	Acute Myeloid L...	GM-CSF	15 Years - 50 Years	Acute Leukemia French Association

Spots Global Cancer Trial Database for priming

Every month we try and update this database with for priming cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for priming

Every month we try and update this database with for priming cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for priming cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.