Study of MK 2206 in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma (AKTIL)

This study has been terminated.
(Regarding the comments of the iDSMB, the sponsor decided to stop the inclusions)
Sponsor:
Collaborator:
National Cancer Institute, France
Information provided by (Responsible Party):
Centre Leon Berard
ClinicalTrials.gov Identifier:
NCT01466868
First received: October 28, 2011
Last updated: July 9, 2014
Last verified: July 2014
  Purpose

The purpose of this study is to evaluate the antitumor efficacy and the safety of MK 2206 in patients with relapsed or refractory diffuse large B cell lymphoma.


Condition Intervention Phase
Diffuse Large B Cell Lymphoma
Drug: MK2206
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of MK 2206 in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma

Resource links provided by NLM:


Further study details as provided by Centre Leon Berard:

Primary Outcome Measures:
  • evaluation of the antitumor activity of MK-2206 in terms of objective response rate (ORR). [ Time Frame: 4 months after the first day of treatment. ] [ Designated as safety issue: No ]
    the objective response rate (ORR) is measured as per 2007 Cheson international response criteria.


Secondary Outcome Measures:
  • safety profile [ Time Frame: during the treatment and up to 3.5 years from the first inclusion ] [ Designated as safety issue: Yes ]
    safety profile is characterized by type, frequency and seriousness of the toxicities showed by patients and graded using CTCAE-V04.

  • overall survival [ Time Frame: from the date of inclusion to the date of death from any cause (up to 3.5 years from the first inclusion) ] [ Designated as safety issue: No ]
  • progression-free survival [ Time Frame: from the date of inclusion to the date of event defined as the first documented disease progression or death from any cause (up to 3.5 years from the first inclusion) ] [ Designated as safety issue: No ]
  • duration of response [ Time Frame: from the time of first documented response (complete response or partial response) until the first documented disease progression or death due to underlying cancer (up to 3.5 years from the first inclusion) ] [ Designated as safety issue: No ]
  • evaluation of the antitumor activity of MK-2206 in terms of objective response rate (ORR). [ Time Frame: 4 months after the first day of treatment ] [ Designated as safety issue: No ]
    the objective response rate (ORR) is measured as per 1999 Cheson international response criteria.


Enrollment: 22
Study Start Date: November 2011
Study Completion Date: June 2014
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MK2206
Treatment is started the day after registration (day 1)until progression according to Cheson international response criteria or documented toxicity.
Drug: MK2206

Treatment will be administered orally once weekly, 2 hours before or after a meal, at day 1, 8, 15, 22 over a 28 day cycle period.

The starting dose level is 200 mg. 2 dose reduction are allowed (135 mg and 90 mg)in case of documented toxicity according to the specific algorithms.


Detailed Description:

Diffuse Large B-cell Lymphoma (DLBCL) is the most frequent subtype of Non-Hodgkin lymphoma (NHL) around the world, in all age groups.

DLBCL is a curable disease and combination of monoclonal antibody against CD20 (rituximab) with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) regimen have improved the prognosis of patients with a 20% increase of the cure rate. For the remaining patients who are not in complete response and/or who relapse after first line therapy, the possibility of cure is dramatically reduced.

As PI3K/AKT/mTOR pathway regulates the expression of cyclin D1, c-Myc and Stat3 proteins, which are involved in the pathogenesis of DLBCL HL), this signalling axis is an emerging therapeutic target for treatment of DLBCL.

One study has shown that the level of p-Akt is an adverse prognostic feature in DLBCL and is found in 52% of tumors samples from DLBCL patients.

Given the fact that AKT is overactivated in about to 52% of DLBCL and is considered as a poor prognosis factor, we postulate that targeting AKT in DLBCL may be an interesting therapeutic strategy.

MK-2206 is an orally selective allosteric inhibitor of AKT developed by MERCK currently highlighted as a promising therapeutic option for cancer patients and under clinical development in several Phase 1 trials.

Therefore, we propose to conduct a Phase II study using a two-stage Simon's design with objective response rate (ORR) as the primary endpoint.

  Eligibility

Ages Eligible for Study:   18 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with histologically confirmed diffuse large B-Cell lymphomas.
  • Patients must have measurable disease.
  • Subjects must have received at least two prior treatment lines.There is no maximal limit on the number of prior therapies

    • Prior treatment must include CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) -like chemotherapy in combination with rituximab. Rituximab used alone is not considered as a separate regimen.
    • Prior treatment could include high dose chemotherapy with autologous stem-cell transplantation if patients had progressed ≥ 3 months after this treatment.
    • Salvage treatment, mobilization chemotherapy, high-dose chemotherapy and planned post-transplant therapy should be considered as one regimen
    • Relapsed or refractory patients who are candidate to high-dose chemotherapy and autologous or allogenic stem cell transplantation are not eligible.
  • Patients must have discontinued all prior therapies for at least 5 times the t1/2 of prior anti-cancer therapies before study entry.
  • Male or female patients, age ≥ 18 years.
  • Life expectancy greater than 4 months.
  • ECOG performance status ≤2.
  • Patients must have normal organ and marrow function as defined below:

    • Absolute neutrophil count ≥ 1.5 x 109/L,
    • Platelet count ≥ 100 x 109/L or ≥75 x 109/L if the bone marrow is involved,
    • AST/ALT ≤ 2.5 x upper limit of normal (ULN) (or ≤ 5.0 x ULN if liver metastasis) direct bilirubin ≤ 1.5ULN
    • Calculated creatinine clearance (Cockcroft-Gault formula) of ≥ 50mL/min
  • Patients must agree to use adequate double contraception
  • Patients must be able to swallow whole tablets.
  • Cardiovascular baseline QTcF≤ 450 msec (male) or QTcF≤470msec (female).
  • Signed written informed consent document.
  • Patients with French Social Security in compliance with the French law relating to biomedical research.

Exclusion Criteria:

  • Tumor tissue sample not available for pathological review.
  • Patients with others than Diffuse large B-Cell Lymphoma histology.
  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
  • Patients who have not recovered from adverse events grade > 1 due to agents administered more than 4 weeks earlier.
  • Patients who are receiving any other investigational agents.
  • Patients with known CNS involvement should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the compliance to the study protocol.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 tablets.
  • Patients with uncontrolled hyperglycemia
  • Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant and breastfeeding women are excluded from this study.
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with MK-2206.
  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption.
  • Patients with clinically important history of liver disease, including viral or other hepatitis or cirrhosis.
  • Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the subject has been free of the disease for ≥ 3 years.
  • Uncontrolled hypertension with resting SBP>140 or resting DBP>90mm Hg
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01466868

Locations
France
Institut Bergonié
Bordeaux, France, 33000
Centre Henri Mondor
Créteil, France
CHRU
Lille, France
Centre Leon Berard
Lyon, France
Institut Paoli Calmettes
Marseille, France, 13000
CHU St Eloi
Montpellier, France
CHU
Nancy, France
CHU de Nantes
Nantes, France
Hôpital Necker
Paris, France, 75014
Hôpital Saint-Louis
Paris, France, 75010
Centre Hospitalier LYON SUD
Pierre Bénite, France
Centre Henri Becquerel
Rouen, France
Institut Gustave Roussy
Villejuif, France
Sponsors and Collaborators
Centre Leon Berard
National Cancer Institute, France
Investigators
Principal Investigator: Hervé Ghesquières, MD Centre Leon Berard, Lyon, France
Principal Investigator: Philippe Cassier, MD Centre Leon Berard
  More Information

Publications:
Hasselblom S, Hansson U, Olsson M, et al.: High immunohistochemical expression of p-AKT predicts inferior survival in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Br J Haematol 149:560-568, 2010
Reeder CB, Gornet MK, Habermann TM, et al.: A phase II trial of the oral mTOR inhibitor Everolimus (RAD001) in relapsed aggressive Non-Hodgkin Lymphoma (NHL), in (ed 110; Abstract 121), 2007
Johnson PB, Ansell SM, Colgan JP, et al.: Phase II trial of the oral mTOR inhibitor everolimus (RAD001) for patients with relapsed or refractory lymphoma, in (ed 25, No. 18S, Abstract 8055), 2007
Smith SM, van Besien K, Karrison T, et al.: Temsirolimus Has Activity in Non-Mantle Cell Non-Hodgkin's Lymphoma Subtypes: The University of Chicago Phase II Consortium. J Clin Oncol, 2010
Casasnovas RO, Meignan M, Berriolo-Riedinger A, et al.: SUVmax reduction improves early prognosis value of interim positron emission tomography scans in diffuse large B-cell lymphoma. Blood 118:37-43, 2011
Meignan M, Gallamini A, Haioun C, et al.: Report on the Second International Workshop on interim positron emission tomography in lymphoma held in Menton, France, 8-9 April 2010. Leuk Lymphoma 51:2171-2180, 2010

Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT01466868     History of Changes
Other Study ID Numbers: AKTIL
Study First Received: October 28, 2011
Last Updated: July 9, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Centre Leon Berard:
Diffuse Large B cell Lymphoma
AKT
MK 2206
objective response rate
progression free survival
overall survival
safety

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin

ClinicalTrials.gov processed this record on August 21, 2014