Clinical Trials /

Akt/ERK Inhibitor ONC201 in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

NCT02420795

Description:

This phase I/II trial studies the side effects and the best dose of v-akt murine thymoma viral oncogene homolog (Akt)/mitogen-activated protein kinase 1(ERK) inhibitor ONC201 and to see how well it works in treating patients with non-Hodgkin's lymphoma that has returned after a period of improvement or does not respond to treatment. Akt/ERK inhibitor ONC201 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Oral ONC201 in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma
  • Official Title: Phase I/II Study of Oral ONC201 in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 2014-0630
  • SECONDARY ID: NCI-2015-00706
  • NCT ID: NCT02420795

Conditions

  • Lymphoma

Interventions

DrugSynonymsArms
ONC201Arm A: ONC201 - Once every 3 Weeks

Purpose

This clinical research study will be done in two parts. The goal of the first part is to find the highest tolerable dose of ONC201 that can be given to patients with relapsed or refractory MCL, DLBCL, and TLCL. Groups of subjects will receive increasing doses of ONC201 by mouth on day 1 of each 21 days cycle or on Day 1 of every week until there are side effects that are not tolerated or a maximum of 625 mg has been found to be tolerable. As a result of new information, it has been decided that subjects in Arm A will continue receiving their dosing every 3 weeks. All other subjects will be dosed weekly. The dose you receive may be too low to have an effect or so high it causes bad side effects. In the second part of this study the highest dose of NC201 will be given to learn if ONC201 can help to control the disease. Please note that this is the first time ONC201 will be given to human subjects.

Detailed Description

      Study Drug Administration:

      If you are found to be eligible to take part in this study, you will take your assigned dose
      of ONC201 capsules by mouth on Day 1 of every 21-day cycle or on Day 1 of every week. You
      will take the study drug in the clinic during Cycle 1.

      You should take ONC201 at about the same time each day and food should not be consumed
      either 2 hours before or 2 hours after you take it. ONC201 should be taken with a glass of
      water as quickly as possible. The capsules should be swallowed whole. Do not attempt to open
      capsules or dissolve them in water. Your study doctor will give you further instructions on
      how to take the study drug.

      If you miss a dose, you can take it up to 6 hours after the time you would have taken it. If
      it is later than 6 hours, you should skip the dose.

      If you vomit a dose and can see all of the capsules you took, you can retake the dose.

      If you vomited and cannot see all of the capsules, do not retake the dose. You will need to
      fill out diary cards with information about when you take ONC201. You should bring the diary
      cards with you to every visit.

      Study Visits:

      On Day 1 of Cycle 1:

        -  You will have a physical and neurological exam.

        -  You will have an EKG 15 minutes, 1 hour, and 2 hours after you take the study drug.

        -  Blood (about 2 tablespoons) will be drawn for routine tests.

        -  Blood (about 2 teaspoons each time) will be drawn for pharmacokinetic (PK) testing
           before you take your study drug, 30 minutes after, 2 hours after, 4 hours after, and 6
           hours after you take it. PK testing measures the level of study drug in your blood at
           different time points.

        -  Blood (about 2 teaspoons) will be drawn for pharmacodynamic (PD) testing before you
           take your study drug. PD testing measures how the level of study drug in your body may
           affect the disease.

      On Day 2 of Cycle 1:

        -  You will have an EKG.

        -  Blood (about 4 teaspoons) will be drawn for PK and PD testing. On Day 3 of Cycle 1,
           blood (about 4 teaspoons) will be drawn for PK and PD testing.

      On Day 8 of Cycle 1:

        -  You will have a physical exam.

        -  Blood (about 2 tablespoon) will be drawn for routine, PK, and PD testing.

        -  You will have an EKG.

      On Day 15 of Cycle 1:

        -  You will have a physical exam.

        -  Blood (about 1 tablespoon) will be drawn for routine tests.

      On Day 1 of Cycles 2 and beyond:

        -  You will have a physical and neurological exam.

        -  Blood (about 3 tablespoons) will be drawn for routine, PK, and PD testing.

        -  If your doctor thinks it is needed, you will have a bone marrow biopsy and aspiration
           to check the status of the disease.

        -  If the study doctor thinks it is needed, you will have a GI endoscopy.

        -  If you are able to become pregnant, blood (about 1½ tablespoons) or urine will be
           collected for a pregnancy test.

      On Day 1 of Cycles 3, 5, and every odd cycle after that, you will have a CT scan and a
      PET/CT scan to check the status of the disease.

      On Days 8 and 15 of Cycles 2 and beyond, blood (about 2 tablespoons) will be drawn for
      routine tests.

      If the study doctor thinks the disease has completely responded to the study treatment, the
      following tests and procedures will be performed to confirm the status of the disease:

        -  You will have a colonoscopy, including a biopsy of any abnormal growths. To collect
           this biopsy, small amounts of tissue are removed with a cutting tool.

        -  You will have a bone marrow biopsy.

        -  If the doctor thinks it is needed, you will have a PET scan. The tests may be repeated
           any time the doctor thinks it is needed.

      Length of Study:

      You may continue taking the study drugs for as long as the doctor thinks it is in your best
      interest. You will no longer be able to take the drugs if the disease gets worse, if
      intolerable side effects occur, or if you are unable to follow study directions. Your
      participation on the study will be over once you have completed the long-term follow-up
      phone calls.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: ONC201 - Once every 3 WeeksExperimentalPhase I starting dose of ONC201 125 mg taken orally Day 1 of every 21-day cycle (enrollment in Arm A stopped February 2016). After end-of-dosing visit, study staff will call participant every 3 months for 1 year.
  • ONC201
Arm B: ONC201 - Once a WeekExperimentalPhase I starting dose of ONC201 125 mg taken orally Day 1 of every week. Dose escalation will continue until MTD is reached for recommended Phase 2 Dose. After end-of-dosing visit, study staff will call participant every 3 months for 1 year.
  • ONC201

Eligibility Criteria

        Inclusion Criteria:

          1. Phase 1 and Phase 2: Confirmed diagnosis of previously treated relapsed and/or
             refractory mantle cell lymphoma, diffuse large B-cell lymphoma. Patients with CNS
             lymphoma are included.

          2. Age >/= 18 years at the time of signing the informed consent.

          3. Patient with leukemia phase (peripheral blood involvement), CNS lymphoma [including
             cerebrospinal fluid (CSF)-only disease], non-measurable disease, gastrointestinal
             (GI) MCL, or bone marrow (BM) MCL are also eligible. Gastrointestinal or bone marrow
             or spleen only patients are allowable and will be analyzed separately.

          4. All adverse events related to prior therapies (chemotherapy, radiotherapy, and/or
             surgery) must be resolved to </= Grade 1, except for alopecia.

          5. Patients must be willing to receive transfusions of blood products.

          6. Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less

          7. Patients must have the following clinical laboratory values: Serum creatinine < 2.0
             mg/dl. ; Serum bilirubin < 1.5 mg/dl; Platelet count > 50,000/mm^3; Absolute
             neutrophil count (ANC) > 1,000/mm^3; Alanine aminotransferase (ALT), or aspartate
             aminotransferase (AST) < 2 x upper limit of normal or < 5 x upper limit of normal if
             hepatic metastases are present.

          8. Willing and able to participate in all study related procedures and therapy including
             swallowing capsules without difficulty.

          9. Females of childbearing potential (FCBP)* must have a negative serum or urine
             pregnancy test and must be willing to use acceptable methods of birth control during
             the study and for 90 days after the last dose of study treatment. Acceptable methods
             of birth control include condoms with birth control foam, birth control pills,
             implantable or injectable birth control, birth control patch, intrauterine device
             (IUD), or diaphragm with spermicidal gel. Male patients must use an effective barrier
             method of contraception (i.e. , condoms with birth control foam or diaphragm with
             spermicidal gel) during the study and for 90 days following the last dose of study
             treatment if sexually active with a female of childbearing potential. Contraception
             must be in place at least 2 weeks prior to initiating study treatment.

         10. #9 cont. - * A female of childbearing potential is a sexually mature woman who: 1)
             has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
             naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at
             any time in the preceding 24 consecutive months).

         11. Patient must be English-speaking [MD Anderson Symptom Inventory (MDASI) completion
             only]

        Exclusion Criteria:

          1. Any serious medical condition including but not limited to, uncontrolled
             hypertension, uncontrolled diabetes mellitus, uncontrolled infection,
             active/symptomatic coronary artery disease, chronic obstructive pulmonary disease
             (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the
             investigators opinion places the patient at unacceptable risk or would prevent the
             subject from signing the informed consent form.

          2. Pregnant or breast feeding females.

          3. Use of any standard/experimental anti-lymphoma drug therapy, including steroids
             (dexamethasone dose >/= 4 mg/day or prednisone >/= 20 mg/day), within 3 weeks of
             initiation of the study or use of any experimental non-drug therapy (e.g., donor
             leukocyte/mononuclear cell infusions) within 56 days of initiation of the study drug
             treatment. Hydroxyurea is permitted up to 24 hours before the first dose of study
             drug in patients with rapidly-proliferating disease.

          4. Prior allogeneic stem cell transplant (SCT) within 16 weeks or autologous SCT within
             8 weeks of initiation of therapy. (Patients that require immunosuppressive therapy
             are not eligible within 60 days of therapy.)

          5. History of human immunodeficiency virus (HIV) infection. Patients with active
             Hepatitis B infection (not including patients with prior Hepatitis B vaccination; or
             positive serum Hepatitis B antibody). Hepatitis C infection is allowed as long as
             there is no active disease and is cleared by GI consultation. HIV screening is not
             required for this study.

          6. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to
             enrollment.

          7. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
             resection of the stomach or small bowel or ulcerative colitis, symptomatic
             inflammatory bowel disease, or partial or complete bowel obstruction, or any other
             gastrointestinal condition that could interfere with the absorption and metabolism of
             ONC201

          8. Major surgery within 4 weeks of initiation of therapy.

          9. The patient has a prior or concurrent malignancy that in the opinion of the
             investigator, presents a greater risk to the patient's health and survival, than of
             the MCL, within the subsequent 6 months at the time of consent. Investigator
             discretion is allowed.

         10. Patients with New York Heart Association (NYHA) Class III and IV heart failure,
             myocardial infarction in the preceding 6 months, and significant conduction
             abnormalities, including but not limited to 2nd degree AV block type II, 3rd degree
             block, QT prolongation (QTc > 500 msec), sick sinus syndrome, ventricular
             tachycardia, symptomatic bradycardia (heart rate < 50 bpm), hypotension, light
             headedness and syncope. Patients with active atrial fibrillation will be excluded.
             The protocol excludes patients who have within the past year had a stent and by
             recommendation of their cardiologist need to stay on anticoagulants such as warfarin
             equivalent vitamin K antagonist.

         11. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to ONC201 or its excipients.

         12. Acute infection requiring treatment (systemic antibiotics, antivirals, or
             antifungals) within 14 days prior to initiation of study.

         13. Active alcoholism or use of recreational drug (evaluated by history taking).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of ONC201 to Determine the Recommended Phase 2 Dose
Time Frame:21 days
Safety Issue:
Description:MTD defined as the highest dose level in which 6 patients have been treated with less than 2 instances of dose limiting toxicity (DLT).

Secondary Outcome Measures

Measure:Overall Response (OR)
Time Frame:21 days
Safety Issue:
Description:Overall response (OR) defined as either complete response (CR) or partial response (PR) observed in the first 3 treatment cycles. International Workshop Standardized Response Criteria for non-Hodgkin's Lymphoma used for measurable disease.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Lymphoma
  • Non-Hodgkin's Lymphoma
  • Relapsed/Refractory
  • NHL
  • Mantle cell lymphoma
  • MCL
  • Diffuse large B-cell lymphoma
  • DLBCL
  • Transformed large cell lymphoma
  • TLCL
  • ONC201
  • Phone call

Last Updated

March 28, 2017