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Diffuse Large B Cell LymphomaPhase 2AKTILNCT01466868

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

A Phase 2 study testing MK2206 in people with Diffuse Large B Cell Lymphoma, run by Centre Leon Berard at 13 sites in France.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 90 years
Conditions the study is for
Diffuse Large B Cell Lymphoma
What is being tested?
MK2206
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
22 participants
Where
13 sitesFrance
Study dates
Nov 2011to Jun 2014
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 90 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 21Show fewer
  • 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.

Who cannot join

  • 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.
Show all 15Show fewer
  • 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

Trial locations and contacts

13 sites in 1 country.

13 sites in 1 country

France13 sites

  • Institut Bergonié

    Bordeaux, 33000

  • Centre Henri Mondor

    Créteil

  • CHRU

    Lille

  • Centre Leon Berard

    Lyon

  • Institut Paoli Calmettes

    Marseille, 13000

  • CHU St Eloi

    Montpellier

  • CHU

    Nancy

  • CHU de Nantes

    Nantes

  • Hôpital Saint-Louis

    Paris, 75010

  • Hôpital Necker

    Paris, 75014

  • Centre Hospitalier LYON SUD

    Pierre-Bénite

  • Centre Henri Becquerel

    Rouen

  • Institut Gustave Roussy

    Villejuif

Other trials in France

About this study

Official title: A Phase II Study of MK 2206 in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma

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.

Read the 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.

Being tested
MK2206
Keywords
Diffuse Large B cell Lymphoma, AKT, MK 2206, objective response rate, progression free survival, overall survival, safety
Medical subject headings
Lymphoma, Large B-Cell, Diffuse

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MK2206Drug

    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.

Study groups in NCT01466868
Study groupRoleWhat they receive
MK2206ExperimentalTreatment is started the day after registration (day 1)until progression according to Cheson international response criteria or documented toxicity.
Receives: Drug: MK2206

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. evaluation of the antitumor activity of MK-2206 in terms of objective response rate (ORR).

    the objective response rate (ORR) is measured as per 2007 Cheson international response criteria.

    Measured: 4 months after the first day of treatment.

Secondary outcomes (5)

  1. safety profile

    safety profile is characterized by type, frequency and seriousness of the toxicities showed by patients and graded using CTCAE-V04.

    Measured: during the treatment and up to 3.5 years from the first inclusion

  2. overall survival

    Measured: from the date of inclusion to the date of death from any cause (up to 3.5 years from the first inclusion)

  3. progression-free survival

    Measured: 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)

  4. duration of response

    Measured: 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)

  5. evaluation of the antitumor activity of MK-2206 in terms of objective response rate (ORR).

    the objective response rate (ORR) is measured as per 1999 Cheson international response criteria.

    Measured: 4 months after the first day of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Nov 2011 (estimated)
  2. Study startNov 2011
  3. Primary completionSep 2013
  4. Study completionJun 2014

Why it stopped: Regarding the comments of the iDSMB, the sponsor decided to stop the inclusions

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
22 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01466868
Sponsor's protocol ID
AKTIL
Acronym
AKTIL
Status last verified
Jul 2014
First submitted
28 Oct 2011
Last updated
10 Jul 2014
Results posted
No
Data monitoring committee
Yes

Publications

  • Thieblemont C, Gisselbrecht C. Second-line treatment paradigms for diffuse large B-cell lymphomas. Curr Oncol Rep. 2009 Sep;11(5):386-93. doi: 10.1007/s11912-009-0052-0.

    PubMed 19679014

  • Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995 Dec 7;333(23):1540-5. doi: 10.1056/NEJM199512073332305.

    PubMed 7477169

  • Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Briere J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. doi: 10.1200/JCO.2010.28.1618. Epub 2010 Jul 26.

    PubMed 20660832

  • Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Ferme C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. doi: 10.1200/JCO.2005.09.131. Epub 2005 May 2.

    PubMed 15867204

  • Lignon J, Sibon D, Madelaine I, Brice P, Franchi P, Briere J, Mounier N, Gisselbrecht C, Faure P, Thieblemont C. Rituximab, dexamethasone, cytarabine, and oxaliplatin (R-DHAX) is an effective and safe salvage regimen in relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk. 2010 Aug;10(4):262-9. doi: 10.3816/CLML.2010.n.055.

    PubMed 20709662

  • Coiffier B. Fourteen years of high-dose CHOP (ACVB regimen): preliminary conclusions about the treatment of aggressive-lymphoma patients. Hamilton Fairley Award Lecture, European Society for Medical Oncology Meeting, Lisbon, November 21, 1994. Ann Oncol. 1995 Mar;6(3):211-7. doi: 10.1093/oxfordjournals.annonc.a059149. No abstract available.

    PubMed 7612487

  • Wilson WH, Dunleavy K, Pittaluga S, Hegde U, Grant N, Steinberg SM, Raffeld M, Gutierrez M, Chabner BA, Staudt L, Jaffe ES, Janik JE. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008 Jun 1;26(16):2717-24. doi: 10.1200/JCO.2007.13.1391. Epub 2008 Mar 31.

    PubMed 18378569

  • Dupuis J, Itti E, Rahmouni A, Hemery F, Gisselbrecht C, Lin C, Copie-Bergman C, Belhadj K, El Gnaoui T, Gaillard I, Kuhnowski F, Meignan M, Haioun C. Response assessment after an inductive CHOP or CHOP-like regimen with or without rituximab in 103 patients with diffuse large B-cell lymphoma: integrating 18fluorodeoxyglucose positron emission tomography to the International Workshop Criteria. Ann Oncol. 2009 Mar;20(3):503-7. doi: 10.1093/annonc/mdn671. Epub 2008 Dec 11.

    PubMed 19074215

  • Shipp MA. Molecular signatures define new rational treatment targets in large B-cell lymphomas. Hematology Am Soc Hematol Educ Program. 2007:265-9. doi: 10.1182/asheducation-2007.1.265.

    PubMed 18024639

  • Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005 Nov 14;24(50):7455-64. doi: 10.1038/sj.onc.1209085.

    PubMed 16288292

  • Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005 Dec;4(12):988-1004. doi: 10.1038/nrd1902.

    PubMed 16341064

  • Steelman LS, Stadelman KM, Chappell WH, Horn S, Basecke J, Cervello M, Nicoletti F, Libra M, Stivala F, Martelli AM, McCubrey JA. Akt as a therapeutic target in cancer. Expert Opin Ther Targets. 2008 Sep;12(9):1139-65. doi: 10.1517/14728222.12.9.1139.

    PubMed 18694380

  • Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005 Dec;17(6):596-603. doi: 10.1016/j.ceb.2005.09.009. Epub 2005 Oct 13.

    PubMed 16226444

  • Gupta M, Ansell SM, Novak AJ, Kumar S, Kaufmann SH, Witzig TE. Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood. 2009 Oct 1;114(14):2926-35. doi: 10.1182/blood-2009-05-220889. Epub 2009 Jul 29.

    PubMed 19641186

  • Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005 Sep;8(3):179-83. doi: 10.1016/j.ccr.2005.08.008.

    PubMed 16169463

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing MK2206 in people with Diffuse Large B Cell Lymphoma, run by Centre Leon Berard at 13 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 10 Jul 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 13 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Regarding the comments of the iDSMB, the sponsor decided to stop the inclusions). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01466868, which also lists 33 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2014.

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