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.
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.
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).
