Akt Inhibitor MK2206 in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

• ClinicalTrials.gov Identifier: NCT01481129
• Recruitment Status: Completed
• First Posted: November 29, 2011
• Results First Posted: April 7, 2017
• Last Update Posted: September 28, 2017
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

This phase II trial is studying how well Akt inhibitor MK2206 works in treating patients with relapsed or refractory diffuse large B-cell lymphoma. Akt inhibitor MK2206 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or disease	Intervention/treatment	Phase
Diffuse Large B Cell Lymphoma	Drug: Akt Inhibitor MK2206; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the antitumor activity of Akt inhibitor MK2206 (MK2206) in terms of objective response rate (ORR) at 4 months (complete response [CR], and partial response [PR]) as per the 2007 International Cheson response criteria.

SECONDARY OBJECTIVES:

I. To evaluate the antitumor activity of MK2206 in terms of ORR at 4 months (CR, unconfirmed complete response [CRu], and PR) as per the 1999 International Cheson response criteria.

II. To determine the duration of response, defined as the time from the date of the best response to the date of progression.

III. To determine the progression-free survival and overall survival of these patients.

IV. To determine the safety of MK2206. V. To identify predictive biomarkers for treatment outcome. (exploratory) VI. To conduct a pharmacodynamic study using FDG-PET scans. (exploratory)

OUTLINE: This a multicenter study.

Patients receive Akt inhibitor MK2206 orally (PO) once weekly on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 22 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of MK-2206 in Patients With Relapsed or Refractory Diffuse Large-B Cell Lymphoma
• Actual Study Start Date: December 2011
• Actual Primary Completion Date: June 2013
• Actual Study Completion Date: June 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (Akt inhibitor MK2206); Patients receive Akt inhibitor MK2206 PO once weekly on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Akt Inhibitor MK2206; Given PO; Other Name: MK2206; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate According to the International Response Criteria for DLBCL (Cheson 2007) [ Time Frame: Up to 4 months ]
   Rate of CR + PR according to Cheson 2007 after 4 months of treatment

Secondary Outcome Measures :

1. Duration of Response [ Time Frame: up to 4 years ]
   Described in responding subjects using descriptive statistics (median, extreme values, etc.).
2. Overall Survival [ Time Frame: From the date of inclusion to the date of death from any cause, assessed up to 4 years ]
   Analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method.
3. Progression-free Survival (PFS) [ Time Frame: From the date of inclusion to the date of first documented disease progression, relapse or death from any cause, assessed up to 4 years ]
   Analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method.
4. Toxicity as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [ Time Frame: Up to 30 days ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologically confirmed diffuse large B-cell lymphoma

  • Relapsed or refractory disease

• Measurable disease

  • At least one measurable lymph node mass that is > 1.5 cm in two perpendicular dimensions and that has not been previously irradiated or has grown since previous irradiation

    • Dominant lymph node masses include up to 6 nodal masses that are clearly measurable in 2 perpendicular dimensions and > 1.5 cm in each dimension
    • Measurement may be by radiographic imaging
    • If there are lymph node masses in the mediastinum or pelvis larger than 1.5 cm in 2 perpendicular dimensions, they should always be chosen as dominant masses
    • The dominant masses should be from as disparate regions of the body as possible
  • Measurable sites of disease are also extra-nodal sites such as splenic nodules and hepatic nodules that are thought to contain lymphoma, and are greater than 1 cm in the longest transverse dimension

• 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
    • Salvage treatment, mobilization chemotherapy, high-dose chemotherapy, and planned post-transplant therapy should be considered as one regimen
  • Relapsed or refractory patients who are candidates for high-dose chemotherapy and autologous or allogeneic stem cell transplantation are not eligible
• Tumor tissue sample must be available for pathological review
• No known CNS involvement
• ECOG performance status < 2 (Karnofsky > 60%)
• Life expectancy > 4 months
• Absolute neutrophil count >= 1,500/µL
• Platelets >= 100,000/µL (>= 75,000/µL if the bone marrow is involved)
• Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)
• AST(SGOT)/ALT(SGPT) =< 2.5 X ULN
• Calculated creatinine clearance >= 50 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Women of child-bearing potential and men must agree to use adequate contraception

• Must be able to swallow whole tablets

  • Nasogastric or G-tube administration is not allowed
  • Tablets must not be crushed or chewed
• Patients with French Social Security in compliance with the French law relating to biomedical research allowed
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK2206 tablets
• Hyperglycemia should be well controlled on oral agents
• Cardiovascular baseline QTcF =< 450 msec (male) or QTcF =< 470 msec (female)
• No 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
• No HIV-positive patients on combination antiretroviral therapy
• No patients with malabsorption syndrome or other condition that would interfere with intestinal absorption
• No patients with clinically important history of liver disease, including viral or other hepatitis or cirrhosis
• No 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
• Must have recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients must have discontinued all prior therapies for at least 5 times the half-life of all prior anticancer therapies before study entry
• Prior treatment could include high-dose chemotherapy with autologous stem-cell transplantation if patients had progressed >= 3 months after this treatment
• No chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C)
• Patients must not be receiving any other investigational agents
• No other investigational or commercial agents or therapies may be administered with the intent to treat the patient's malignancy
• No concurrent radiotherapy

Contacts and Locations

Locations

France

Hopitaux de Paris

Vellefaux, Paris, France, 75010

Institut Bergonie Cancer Center

Bordeaux, France, 33076

Henri Mondor University-Hospital Center

Creteil, France, 94000

Hospital Claude Huriez Chru

Lille, France, 59037

Centre Leon Berard

Lyon, France, 69373

Institut Paoli Calmettes

Marseille, France, 13273

Hopital Saint Louis

Paris, France, 75010

Centre Hospitalier Lyon-Sud

Pierre Benite, France, 69310

Institut Gustave Roussy

Villejuif, France, 94805

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Herve Ghesquieres; Centre Leon Berard

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01481129
• Other Study ID Numbers: NCI-2012-00081; NCI-2012-00081 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); LEONB-ET-2011-041; 2011-001970-25; CDR0000716384; ET-2011-041 ( Other Identifier: Centre Leon Berard ); 9022 ( Other Identifier: CTEP )
• First Posted: November 29, 2011
• Results First Posted: April 7, 2017
• Last Update Posted: September 28, 2017
• Last Verified: August 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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