Study of Venetoclax With the mIDH1 Inhibitor Ivosidenib (AG120) in IDH1-Mutated Hematologic Malignancies
| Status: | Recruiting |
|---|---|
| Conditions: | Blood Cancer, Hematology, Hematology |
| Therapuetic Areas: | Hematology, Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 1/9/2019 |
| Start Date: | March 19, 2018 |
| End Date: | September 2019 |
| Contact: | Courtney DiNardo, MD |
| Email: | cdinardo@mdanderson.org |
| Phone: | 713-794-1141 |
Phase Ib/II Investigator Sponsored Study of the IDH1-Mutant Inhibitor Ivosidenib (AG120) With the BCL2 Inhibitor Venetoclax in IDH1-Mutated Hematologic Malignancies
There are 2 parts to this clinical research study: Part 1 (dose escalation) and Part 2 (dose
expansion).
The goal of Part 1 of this clinical research study is to find the highest tolerable dose of
the combination of ivosidenib (AG-120) and venetoclax that can be given to patients with
relapsed (has come back) or refractory (has not responded to treatment) acute myeloid
leukemia (AML) with an IDH1 mutation (a type of genetic change).
The goal of Part 2 is to learn if the highest tolerable dose of ivosidenib and venetoclax
found in Part 1 can help to control the disease.
The safety of this drug combination will be studied in both parts.
This is an investigational study. Ivosidenib is not FDA approved or commercially available.
Venetoclax is FDA approved and commercially available for the treatment of a certain type of
chronic lymphocytic leukemia (CLL). It is considered investigational to use ivosidenib in
combination with venetoclax to treat AML.
The study doctor can explain how the study drugs are designed to work.
Up to 48 patients will be enrolled on this study. All will take part at MD Anderson.
expansion).
The goal of Part 1 of this clinical research study is to find the highest tolerable dose of
the combination of ivosidenib (AG-120) and venetoclax that can be given to patients with
relapsed (has come back) or refractory (has not responded to treatment) acute myeloid
leukemia (AML) with an IDH1 mutation (a type of genetic change).
The goal of Part 2 is to learn if the highest tolerable dose of ivosidenib and venetoclax
found in Part 1 can help to control the disease.
The safety of this drug combination will be studied in both parts.
This is an investigational study. Ivosidenib is not FDA approved or commercially available.
Venetoclax is FDA approved and commercially available for the treatment of a certain type of
chronic lymphocytic leukemia (CLL). It is considered investigational to use ivosidenib in
combination with venetoclax to treat AML.
The study doctor can explain how the study drugs are designed to work.
Up to 48 patients will be enrolled on this study. All will take part at MD Anderson.
Study Groups:
If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you join this study. Up to 5 groups of 6 participants will be enrolled in
Part 1 of the study, and up to 24 participants will be enrolled in Part 2.
If you are enrolled in Part 1, the dose levels of venetoclax you receive will depend on when
you join this study. The first group of participants will receive the lowest dose levels of
venetoclax. Each new group will receive a higher dose of venetoclax than the group before it,
if no intolerable side effects were seen. This will continue until the highest tolerable dose
of venetoclax is found.
All participants will receive the same dose level of ivosidenib.
If you are enrolled in Part 2, you will receive ivosidenib and venetoclax at the highest dose
that was tolerated in Part 1.
Study Drug Administration:
Each study cycle is 28 days.
You will take venetoclax by mouth 1 time each day on Days 1-14 of each cycle. You should take
your dose with about 1 cup (8 ounces) of water and within 30 minutes of eating. Your dose of
venetoclax will slowly increase over the first 3-5 days until you receive the full dose. Your
dose level of venetoclax may change while on study, if needed. This will be discussed with
you.
You will take ivosidenib by mouth 1 time each day starting with Day 15 of Cycle 1. You may
take your dose with or without food.
You will record all of your doses in a study diary, which you should bring with you to each
study visit. If you miss a dose and it is within 6 hours of the missed dose, you may take it.
If you vomit after taking a dose, or more than 6 hours has passed since you missed a dose,
you must not make-up the dose. Continue taking the next dose at your regular time.
During Cycle 1, you will be admitted into the hospital as an inpatient for at least the first
5-7 days of your study treatment. During this time, you will also be given standard drugs to
help prevent . You may ask the study staff for information about how the drugs are given and
their risks. TLS happens when breakdown products of the cancer cells enter the blood stream
(causing weakness, low blood pressure, muscle cramps, kidney damage, and/or other organ
damage).You will stay in the hospital for the first 5-7 days of study treatment. If the
doctor thinks it is needed, you may need to stay in the hospital longer.
Length of Treatment:
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 study 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 after the follow-up visits.
TLS Testing:
During Cycle 1, while you are admitted to the hospital to receive your first doses of
venetoclax, blood (about 2 tablespoons each time) will be drawn to measure your levels of
uric acid, potassium, creatinine, phosphorus, and calcium, and to check for symptoms of TLS
at the following timepoints:
- Before each dose.
- 6-8 hours after each dose.
- 24 hours after each dose.
Study Visits:
On Days 1-4 and 8 of Cycle 1:
- Blood (about 3 tablespoons) will be drawn for routine testing. If it was not done at
screening, on Day 1 only, this blood sample will also be used for biomarker testing.
- On Days 1 and 8 only, you will have a physical exam.
On Day 22 of Cycle 1:
- You will have a physical exam.
- Blood (about 3 tablespoons) will be drawn for routine testing.
On Day 14 of Cycles 1 and 2, blood (about 1 teaspoon each time) will be drawn for PK testing
before the dose and then 6 more times over the next 24 hours after the dose.
On Day 15 of Cycles 1 and 2:
- You will have a physical exam.
- Blood (about 1 tablespoon) will be drawn for routine testing.
- You will have an EKG.
On Day 28 (+/- 4 days ) of Cycle 1 and every odd-numbered cycle (+/- 7 days) after that
(Cycles 3, 5, 7, and so on) for up to 1 year:
- You will have a bone marrow aspirate/biopsy for IDH1, cytogenetic, and biomarker
testing.
- Blood (about 1 tablespoon) will be drawn for biomarker testing.
On Day 1 of Cycle 2 and every cycle after that:
- You will have a physical exam.
- Blood (about 3 tablespoons) will be drawn for routine testing.
- On Day 1 of Cycle 2 only, you will have an EKG.
On Day 1 of Cycle 3, you will have an EKG.
End-of-Treatment (Final) Visit:
When you have received your last dose of study drug:
- You will have a physical exam.
- Blood (about 4 tablespoons) will be drawn for routine and biomarker testing.
- You will have a bone marrow aspirate/biopsy for IDH1, cytogenetic, and biomarker
testing.
- You will have an EKG.
End-of- Study Visit:
About 30 days after your last dose of study drug:
- You will have a physical exam.
- Blood (about 4 tablespoons) will be drawn for routine and biomarker testing.
If at any point the study doctor thinks it is needed, you will have a bone marrow
aspirate/biopsy to check the status of the disease.
Long-Term Follow-Up:
One (1) time each month for 3 years after the last participant has enrolled onto the study, a
member of the study staff will contact you to ask how you are doing. This follow-up will take
place either by phone or at a regularly scheduled clinic visit. If you are contacted by
phone, the call should last about 15 minutes.
If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you join this study. Up to 5 groups of 6 participants will be enrolled in
Part 1 of the study, and up to 24 participants will be enrolled in Part 2.
If you are enrolled in Part 1, the dose levels of venetoclax you receive will depend on when
you join this study. The first group of participants will receive the lowest dose levels of
venetoclax. Each new group will receive a higher dose of venetoclax than the group before it,
if no intolerable side effects were seen. This will continue until the highest tolerable dose
of venetoclax is found.
All participants will receive the same dose level of ivosidenib.
If you are enrolled in Part 2, you will receive ivosidenib and venetoclax at the highest dose
that was tolerated in Part 1.
Study Drug Administration:
Each study cycle is 28 days.
You will take venetoclax by mouth 1 time each day on Days 1-14 of each cycle. You should take
your dose with about 1 cup (8 ounces) of water and within 30 minutes of eating. Your dose of
venetoclax will slowly increase over the first 3-5 days until you receive the full dose. Your
dose level of venetoclax may change while on study, if needed. This will be discussed with
you.
You will take ivosidenib by mouth 1 time each day starting with Day 15 of Cycle 1. You may
take your dose with or without food.
You will record all of your doses in a study diary, which you should bring with you to each
study visit. If you miss a dose and it is within 6 hours of the missed dose, you may take it.
If you vomit after taking a dose, or more than 6 hours has passed since you missed a dose,
you must not make-up the dose. Continue taking the next dose at your regular time.
During Cycle 1, you will be admitted into the hospital as an inpatient for at least the first
5-7 days of your study treatment. During this time, you will also be given standard drugs to
help prevent . You may ask the study staff for information about how the drugs are given and
their risks. TLS happens when breakdown products of the cancer cells enter the blood stream
(causing weakness, low blood pressure, muscle cramps, kidney damage, and/or other organ
damage).You will stay in the hospital for the first 5-7 days of study treatment. If the
doctor thinks it is needed, you may need to stay in the hospital longer.
Length of Treatment:
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 study 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 after the follow-up visits.
TLS Testing:
During Cycle 1, while you are admitted to the hospital to receive your first doses of
venetoclax, blood (about 2 tablespoons each time) will be drawn to measure your levels of
uric acid, potassium, creatinine, phosphorus, and calcium, and to check for symptoms of TLS
at the following timepoints:
- Before each dose.
- 6-8 hours after each dose.
- 24 hours after each dose.
Study Visits:
On Days 1-4 and 8 of Cycle 1:
- Blood (about 3 tablespoons) will be drawn for routine testing. If it was not done at
screening, on Day 1 only, this blood sample will also be used for biomarker testing.
- On Days 1 and 8 only, you will have a physical exam.
On Day 22 of Cycle 1:
- You will have a physical exam.
- Blood (about 3 tablespoons) will be drawn for routine testing.
On Day 14 of Cycles 1 and 2, blood (about 1 teaspoon each time) will be drawn for PK testing
before the dose and then 6 more times over the next 24 hours after the dose.
On Day 15 of Cycles 1 and 2:
- You will have a physical exam.
- Blood (about 1 tablespoon) will be drawn for routine testing.
- You will have an EKG.
On Day 28 (+/- 4 days ) of Cycle 1 and every odd-numbered cycle (+/- 7 days) after that
(Cycles 3, 5, 7, and so on) for up to 1 year:
- You will have a bone marrow aspirate/biopsy for IDH1, cytogenetic, and biomarker
testing.
- Blood (about 1 tablespoon) will be drawn for biomarker testing.
On Day 1 of Cycle 2 and every cycle after that:
- You will have a physical exam.
- Blood (about 3 tablespoons) will be drawn for routine testing.
- On Day 1 of Cycle 2 only, you will have an EKG.
On Day 1 of Cycle 3, you will have an EKG.
End-of-Treatment (Final) Visit:
When you have received your last dose of study drug:
- You will have a physical exam.
- Blood (about 4 tablespoons) will be drawn for routine and biomarker testing.
- You will have a bone marrow aspirate/biopsy for IDH1, cytogenetic, and biomarker
testing.
- You will have an EKG.
End-of- Study Visit:
About 30 days after your last dose of study drug:
- You will have a physical exam.
- Blood (about 4 tablespoons) will be drawn for routine and biomarker testing.
If at any point the study doctor thinks it is needed, you will have a bone marrow
aspirate/biopsy to check the status of the disease.
Long-Term Follow-Up:
One (1) time each month for 3 years after the last participant has enrolled onto the study, a
member of the study staff will contact you to ask how you are doing. This follow-up will take
place either by phone or at a regularly scheduled clinic visit. If you are contacted by
phone, the call should last about 15 minutes.
Inclusion Criteria:
1. Age >/= 18 years.
2. Eastern Cooperative Oncology Group (ECOG) performance status of
3. IDH1-R132 mutated disease status as assessed by local laboratory. 2HG-producing IDH1
variants outside of R132 (i.e. R100) may be eligible after discussion with the PI.
4. Relapsed/refractory AML. Treatment-naïve patients who are not eligible for standard
induction chemotherapy may also be eligible after discussion with the PI if in the
best interest of the patient. Patients with high-risk MDS or MPN (defined as >/ = 10%
bone marrow blasts) may also be eligible after discussion with the PI.
5. Baseline cardiac ejection fraction must be >/= 40 %
6. Adequate hepatic function (direct bilirubin unless deemed to be related to underlying leukemia.
7. Adequate renal function including creatinine clearance >/= 30 ml/min based on the
Cockcroft-Gault equation.
8. Willing and able to provide informed consent
9. In the absence of rapidly proliferative disease, the interval from prior treatment to
time of initiation will be at least 7 days for cytotoxic or non-cytotoxic
(immunotherapy) agents.
10. Male subjects must agree to refrain from unprotected sex and sperm donation from
initial study drug administration until 90 days after the last dose of study drug
administration until 90 days after the last dose of study drug
Exclusion Criteria:
1. Patients with known allergy or hypersensitivity to AG120 or venetoclax.
2. Patients who have previously received either AG120 or venetoclax
3. Patients with any concurrent uncontrolled clinically significant medical condition,
including infection, laboratory abnormality, or psychiatric illness which could place
the patient at unacceptable risk of study treatment.
4. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted
during study with the following exceptions (1) intrathecal chemotherapy for
prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea and/or one
dose of cytarabine (up to 2 g/m2) or hydroxyurea for patients with rapidly
proliferative disease is allowed before the start of study therapy and for the first
four weeks on therapy.
5. Patients receiving concomitant treatment with strong CYP3A4 inhibitors within 3 days
of start of study therapy (including posaconazole and voriconazole)
6. Patients receiving concomitant strong CYP3A inducers (avasimibe, carbamazepine,
phenytoin, rifampin, rifabutin, St. John's wort) within 3 days of start of study
therapy.
7. Patients with active graft-versus-host-disease (GVHD) status post stem cell
transplant, i.e. patients requiring therapy more than chronic steroid
immunosuppression and/or phototherapy for chronic skin GVHD will be excluded
8. Patients with any severe gastrointestinal or metabolic condition which could interfere
with the absorption of oral study medications.
9. Patients with a concurrent active malignancy under treatment.
10. QTc interval using Fridericia's formula (QTcF) >/= 450 msec. Bundle branch block and
prolonged QTc interval are permitted after discussion with the PI
11. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known HIV infection.
12. Subject has a white blood cell count > 25 x 10^9/L. (Note: Hydroxyurea is permitted to
meet this criterion.)
13. Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy
test, or women of childbearing potential who are not willing to maintain adequate
contraception. a) Appropriate highly effective method(s) of contraception include oral
or injectable hormonal birth control, IUD, and double barrier methods (for example a
condom in combination with a spermicide).
We found this trial at
1
site
1515 Holcombe Blvd
Houston, Texas 77030
Houston, Texas 77030
713-792-2121
University of Texas M.D. Anderson Cancer Center The mission of The University of Texas MD...
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