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

Sponsor

Centre Leon Berard (Other)

Overall Status

Terminated

CT.gov ID

NCT01466868

Collaborator

National Cancer Institute, France (Other)

Enrollment

Locations

Arm

Duration (Months)

1.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Diffuse Large B Cell Lymphoma	Drug: MK2206	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

22 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Nov 1, 2011

Actual Primary Completion Date :

Sep 1, 2013

Actual Study Completion Date :

Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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.

Arm

Intervention/Treatment

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.

Outcome Measures

Primary Outcome Measures

evaluation of the antitumor activity of MK-2206 in terms of objective response rate (ORR). [4 months after the first day of treatment.]
the objective response rate (ORR) is measured as per 2007 Cheson international response criteria.

Secondary Outcome Measures

safety profile [during the treatment and up to 3.5 years from the first inclusion]
safety profile is characterized by type, frequency and seriousness of the toxicities showed by patients and graded using CTCAE-V04.
overall survival [from the date of inclusion to the date of death from any cause (up to 3.5 years from the first inclusion)]
progression-free survival [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)]
duration of response [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)]
evaluation of the antitumor activity of MK-2206 in terms of objective response rate (ORR). [4 months after the first day of treatment]
the objective response rate (ORR) is measured as per 1999 Cheson international response criteria.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	Country	Postal Code
1	Institut Bergonié	Bordeaux	France	33000
2	Centre Henri Mondor	Créteil	France
3	CHRU	Lille	France
4	Centre Leon Berard	Lyon	France
5	Institut Paoli Calmettes	Marseille	France	13000
6	CHU St Eloi	Montpellier	France
7	CHU	Nancy	France
8	CHU de Nantes	Nantes	France
9	Hôpital Saint-Louis	Paris	France	75010
10	Hôpital Necker	Paris	France	75014
11	Centre Hospitalier LYON SUD	Pierre Bénite	France
12	Centre Henri Becquerel	Rouen	France
13	Institut Gustave Roussy	Villejuif	France