Trial of Pimasertib in Hematological Malignancies

Leukemia, Myeloid, Acute Clinical Trial

Official title:

Phase II Trial With Safety-Run-In of MEK Inhibitor MSC1936369B in Subjects With Poor Prognosis Acute Myeloid Leukemia and Other Hematological Malignancies

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00957580
• Other study ID #: EMR200066_002
• Secondary ID: 2009-010866-49
• Status: Terminated
• Phase: Phase 2
• First received: August 11, 2009
• Last updated: February 7, 2014
• Start date: September 2009
• Est. completion date: December 2012

Study information

• Verified date: February 2014
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This is an open-label, multi-center, dose-escalation trial of pimasertib in blood and bone marrow cancers. The trial will be conducted in two parts:

Part 1 (safety run-in period): Will determine the maximum tolerated dose (MTD) of the study drug in subjects with advanced hematological malignancies.

Part 2: Will assess the anti-leukemic activity of the study drug in older subjects with newly diagnosed poor prognosis Acute Myeloid Leukemia (AML) who are not candidates for intensive chemotherapy.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 80
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

Part 1:

1. Subjects with one of the following conditions:

• Primary or secondary AML, pathologically confirmed according to World Health Organization (WHO) classification who meet at least one of the following conditions:

1. Subjects with second or subsequent relapse after standard therapy, for whom no established treatment options are available

2. Subjects refractory to available therapies, for example, who failed to achieve complete response (CR) after 2 induction chemotherapy treatments

3. Newly-diagnosed older subjects (greater than or equal to 75 years of age), not candidates for intensive chemotherapy

• Subjects with myelodysplastic syndrome (MDS), International Prognostic Scoring System (IPSS) Int-2 or high risk who are resistant or intolerant to standard treatment and not candidates for transplantation

• Subjects with relapsed or refractory multiple myeloma (MM), who have failed or are intolerant to at least two prior therapies including thalidomide, lenalidomide and bortezomib

• Subjects with advanced myeloproliferative disorders (MPD) for whom no established treatment options are available

• Subjects with acute lymphocytic leukemia (ALL), relapsed, refractory or intolerant to standard treatment and for whom no effective treatment options are available

2. Age greater than or equal to 18 years

3. Subjects have read and understood the Informed Consent Form and are willing and able to give informed consent. They fully understand requirements of the trial and are willing to comply with all trial visits and assessments

4. Subjects and their partners must be willing to avoid pregnancy during the trial and until 1 month after the last trial drug administration. Subjects must therefore be willing to use adequate contraception as approved by the Investigator, two barrier methods or one barrier method with spermicide or intrauterine device, 2 weeks before, during the trial and 1 month after. The use of hormonal contraceptives should be avoided due to a possible drug-drug interaction in female subjects of childbearing age

Part 2:

1. Subjects (male and female) with newly diagnosed primary or secondary AML pathologically confirmed according to WHO classification who have not been exposed to any prior therapy for AML with the exception of:

• Emergency leukapheresis and

• Emergency treatment for hyperleukocytosis with hydroxyurea that is allowed until 24 hours before the start of the trial treatment. Prior therapy for pre-existing hematological conditions, for example, MDS or MPD, including but not limited to hypomethylating agents, is also allowed until at least 2 weeks or 5 half-lives of that agent before the first dose of MSC1936369B

2. Subjects meet at least one of the following conditions:

• Age greater than or equal to 75 years OR

• Age greater than or equal to 60 and less than 75 years with at least one of the following poor prognostic factors:

• Secondary AML, as determined by known and documented exposure to leukemogenic therapy or environmental toxin or antecedent history of MDS or MPD according to WHO criteria for at least 3 months prior to trial entry, with prior bone marrow aspirate, biopsy and peripheral blood smear documenting the diagnosis

• At least one of the following unfavorable cytogenetic abnormalities:

del(5q), -5, -7, del(7q), abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) or complex karyotypes (greater than or equal to 3 unrelated abnormalities)

• Eastern Cooperative Oncology Group (ECOG) status 2

3. Subjects have read and understood the Informed Consent Form and are willing and able to give informed consent. They fully understand requirements of the trial and are willing to comply with all trial visits and assessments

4. Subjects and their partners must be willing to avoid pregnancy during the trial and until 1 month after the last trial drug administration. Subjects must therefore be willing to use adequate contraception as approved by the Investigator such as two barrier methods or one barrier method with spermicide or intrauterine device, 2 weeks before, during the trial and 1 month after. The use of hormonal contraceptives should be avoided due to a possible drug-drug interaction in female subjects of childbearing age

Exclusion Criteria:

Part 1 and Part 2:

1. ECOG performance status 3 or greater

2. Hyperleukocytosis with greater than 30 x 10 to the ninth power per liter leukemia blasts in peripheral blood

3. Acute promyelocytic leukemia [t(15;17)]

4. Administration of any antineoplastic therapy within at least 2 weeks or 5 half lives of that therapy of the first MSC1936369B dose; except the use of hydroxyurea as permitted in inclusion criteria

5. Participation in other clinical trials within at least 2 weeks of the first MSC1936369B dose

6. Clinical evidence of active central nervous system leukemia

7. Active and uncontrolled infection including but not limited to known infection with human immunodeficiency virus (HIV), active hepatitis B or hepatitis C. Subjects with an infection receiving treatment with antibiotics may be entered into the trial if they are afebrile and hemodynamically stable for 48 hours prior to trial entry

8. Major surgery within two weeks prior to trial entry

9. Liver function tests above the following limits at screening: total bilirubin >1.5 x upper limit of normal (ULN) unless related to Gilbert's syndrome or hemolysis, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x ULN, or for subjects with liver involvement AST and/or ALT >5 x ULN

10. Serum creatinine >1.5 x ULN and /or creatinine clearance <30 milliliter per minute (mL/min) at screening

11. International normalized ratio (INR) greater than 1.5 x ULN unless on treatment with warfarin

12. For female subjects: pregnant or breast-feeding

13. History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product

14. Has significant cardiac conduction abnormalities and/or pacemaker

15. Has retinal degenerative disease (heredity retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion and/or any medically relevant abnormal findings at the initial ophthalmologic examination

16. Subjects with solid tumors, for whom the Investigator has clinical suspicion of active disease at the time of enrolment. Patients with adequately treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are eligible for this study

17. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such

18. Other significant disease that in the Investigator's opinion would exclude the subject from the trial

19. Legal incapacity or limited legal capacity

Study Design

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

Related Conditions & MeSH terms

• Hematologic Neoplasms
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Pimasertib
Pimasertib will be administered orally on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The starting dose will be 8 mg twice daily. The dose escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
• Pimasertib
Pimasertib will be administered orally on Days 1 to 21 of a 28-day cycle. The starting dose will be 8 mg twice daily. The dose escalation will proceed until MTD is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
• Pimasertib
Pimasertib will be administered orally on Days 1-28 of a 28-day cycle. The starting dose will be 8 mg twice daily. The dose escalation will proceed until MTD is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
• Pimasertib
Pimasertib will be administered orally twice daily on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. Dose will be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
• Pimasertib
Pimasertib will be administered orally twice daily on Days 1 to 21 of a 28-day cycle. Dose will be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Locations

Country	Name	City	State
France	Hospital Edouard Herriot, Service d'Hematologie Clinique	Lyon Cedex
France	Hospital Hotel Dieu, Service D'Hematologie	Nantes	Cedex
France	Hospital Saint Louis, Service des Maladies du Sang	Paris
France	CHU du Haut-Leveque, Service des Maladies du Sang Unite de Recherche Clinique	Pessac
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	University of Texas - MD Anderson Cancer Center	Houston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
EMD Serono

Countries where clinical trial is conducted

United States,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Number of subjects with Dose Limiting Toxicities (DLTs)		Up to Day 29 of Cycle 1	Yes
Primary	Part 2: Percentage of Subjects with Best Overall Response		Day 29 of every 29-day cycle until progression reported between day of first patient randomized, September 2009, until cut-off date, December 2012	No
Secondary	Part 1: Number of Subjects with Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation		3 years	Yes
Secondary	Part 1: Maximum Concentration (Cmax) of Pimasertib		Days 1, 3-5, 8, 19, 26, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 1 and Days 1, 3-5, 8, 19-21, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 2 and 3	No
Secondary	Part 1: Time to Reach Maximum Concentration (tmax) and Apparent Terminal Half-Life (t1/2) of Pimasertib		Days 1, 3-5, 8, 19, 26, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 1 and Days 1, 3-5, 8, 19-21, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 2 and 3	No
Secondary	Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) and Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib		Days 1, 3-5, 8, 19, 26, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 1 and Days 1, 3-5, 8, 19-21, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 2 and 3	No
Secondary	Part 1: Apparent Oral Clearance (CL/f) of Pimasertib		Days 1, 3-5, 8, 19, 26, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 1 and Days 1, 3-5, 8, 19-21, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 2 and 3	No
Secondary	Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib		Days 1, 3-5, 8, 19, 26, and 29 in Cycle 1 and Day 1 in Cycle 1 and 2 for Regimen 1 and Days 1, 3-5, 8, 19-21, and 29 in Cycle 1 and Day 1 in Cycle 1 and 2 for Regimen 2 and 3	No
Secondary	Part 1: Percentage of Subjects with Best Overall Response		Day 29 of every alternate 29-day cycle until progression reported between day of first patient randomized, September 2009, until cut-off date, December 2012	No
Secondary	Part 2: Number of Subjects with TEAEs, Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation		3 years	Yes