Study to Evaluate the Safety and Tolerability of IACS-010759 in Subjects With Advanced Solid Tumors and Lymphoma



Status:Recruiting
Conditions:Breast Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - Any
Updated:3/24/2019
Start Date:November 13, 2017
End Date:November 2023
Contact:Timothy A. Yap, PHD, MBBS
Email:tyap@mdanderson.org
Phone:713-563-1784

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A Phase 1 Study to Evaluate the Safety and Tolerability of IACS-010759 in Subjects With Advanced Solid Tumors and Lymphoma

This clinical research study has 2 parts: dose escalation and dose expansion.

The goal of dose escalation in this clinical research study is to find the recommended dose
of IACS-010759 that can be given to patients with advanced solid tumors or lymphoma.

The goal of dose expansion in this clinical research study is to learn if the dose of
IACS-010759 found in the dose escalation part of the study is the best dose to use in future
studies using IACS-010759 in patients with advanced solid tumors or lymphoma.

The safety of this drug will also be studied.

This is an investigational study. IACS-010759 is not FDA approved or commercially available.
It is currently being used for research purposes only. The study doctor can explain how the
study drug is designed to work.

Up to 60 participants will take part in this study. All will be enrolled 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 joined the study. Up to 5 groups of 3-6 participants will be enrolled
in the dose escalation part of the study. Up to 30 participants will be enrolled in dose
expansion.

If you are enrolled in dose escalation, the dose of IACS-010759 you receive will depend on
when you join this study. The first group of participants will receive the lowest dose level
of IACS-010759. Each new group will receive a higher dose of IACS-010759 than the group
before it, if no intolerable side effects were seen. This will continue until the highest
tolerable dose of IACS-010759 is found.

If you are enrolled in the dose expansion part of the study, you will receive the dose level
of IACS-010759 that was found to be the best dose in the escalation part of the study.

In the dose expansion part of the study, 3 groups of 10 participants each will be enrolled.
Each group will be made up of participants with different disease types (breast cancer,
pancreatic cancer, and cancers with tumors that can be safely biopsied on several occasions
[the Biopsy Expansion Cohort]).

Study Drug Administration:

Each study cycle is 21 days. You will take the drug in 2 phases: Induction Phase and
Maintenance Phase.

In the Induction Phase, you will take IACS-010759 by mouth one (1) time every day on Days 1-7
of Cycle 1. At the end of the Induction Phase, you will move on to the Maintenance Phase.

During the Maintenance Phase, you will take IACS-010759 by mouth twice per week. The study
doctor will tell you when to take your dose.

You should take each dose with about a cup (8 ounces) of water and at least 1 hour before or
2 hours after a meal. If you miss a dose, you should not take another dose until the next
scheduled time.

Length of Study:

You may continue to take IACS-010759 up to 12 cycles or longer if the study doctor thinks it
is in your best interest. You will no longer be able to take the study drug if the disease
gets worse, if intolerable side effects occur, or if you are unable to follow study
directions. It is possible that you may need to stop taking the study drug for a period of
time and then re-start it. The study doctor will tell you if this is the case.

Your participation on this study will be over after long-term follow-up (described below).

Study Visits:

On Day 1 of Cycle 1:

- You will have a physical exam.

- Blood (about 7-8 teaspoons each time) will be drawn before and after the dose for
acid/base level tests, for PK testing and for PD testing.

- Blood (up to 2 teaspoons) will be drawn for tumor genetic testing.

- You will have an EKG before the dose after the dose.

On Days 4, 11, and 18 of Cycle 1, blood (about 1 teaspoons each time) will be collected for
acid/base level. Blood (about 1 teaspoon each time) will also be collected for PK testing. On
Day 11 and 18, blood for PK testing will be drawn before and 4 hours after your study drug
dose.

On Day 7 and 15 of Cycle 1:

- You will have a physical exam.

- You will have an EKG. Blood (about 3-4 teaspoons) will be drawn before the dose to check
how well your organs function and for routine and acid/base level testing. On Day 7
only, blood (about 1 teaspoon) will also be drawn for acid/base level testing 4 hours
after your study drug dose.

- Blood (about 1 teaspoon each time) will be drawn before the dose and then 5 more times
over the next 12 hours on Day 7 and before and after the dose on Day 15 for PK testing.

- On Day 15 only, blood (about 6 teaspoons) will be drawn for PD testing.

- Urine will be collected before the dose for routine tests.

On Day 8 of Cycle 1:

- Blood (about 7 teaspoons) will be drawn for acid/base level and PD testing.

- Blood (about 1 teaspoon each time) will be drawn before and after the dose for PK
testing.

- If you are in the Biopsy Expansion Cohort, you will also have a tumor biopsy.

On Day 1, 8, and 15 of Cycle 2:

- You will have a physical exam.

- Blood (about 7-8 teaspoons each time) will be drawn for routine tests, acid/base level
tests, to check how well your organs are functioning, and for PD testing.

- On Day 1, blood (1 teaspoon each time) will be drawn before and after the dose for PK
testing.

- On Day 15, blood (1 teaspoon each time) will be drawn before the dose and again 6 more
times over the next 24 hours for PK testing.

- Urine will be collected for routine tests.

On Day 21 of Cycle 2:

- You will have a PET, MRI, CT scan or X-ray.

- You will have a physical exam.

- If your doctor decides it is needed, blood (up to 1/2 teaspoon) will be drawn for tumor
marker testing.

- Blood (about 3-4 teaspoons) will be drawn to check how well your organs are functioning
and for routine acid/base level and PK testing.

- Urine will be collected for routine tests.

On Day 21 of Cycles 3 and beyond:

- You will have a physical exam.

- Blood (about 3-4 teaspoons) will be drawn to check how well your organs are functioning
and for routine acid/base level and PK testing.

- Urine will be collected for routine tests.

Every 2 cycles while you are on study, you will have blood drawn to test for relevant tumor
markers, PD testing and a CT scan performed. After you have received the study drug for 6
months, your doctor may decide that you can have these tests performed once every 3 cycles
(instead of every 2 cycles). If you have a response to the study drug, you will have CT scans
performed again within 4 weeks.

If the study doctor stops and re-starts your dose of study drug, the following will be
performed:

°Blood (about 3-4 teaspoons) will be drawn for acid/base level and PK testing. This blood
draw will also be used to check how well your organs are functioning.

If the study doctor lowers your dose of study drug, the following will be performed when you
start taking the lower dose:

°Blood (about 1 teaspoon) will be drawn for PK testing.

End-of-Study Visit:

About 30 days after your last dose of the study drug:

- You will have a physical exam.

- You will have a PET, MRI, CT scan or X-ray.

- Blood (about 9-10 teaspoons) and urine will be collected for routine tests, acid/base
level tests, and PK and PD testing. Blood for PK and PD testing may continue to be
collected, if possible, every 4 days for up to 4 weeks after your last dose of study
drug.

- If you are in the Biopsy Expansion Cohort, you will have a tumor biopsy.

If you are unable to return to the clinic for the visit, this testing can be performed by a
local doctor and the results will be sent to the study doctor. The research nurse will call
you to ask about your health. These calls should last about 5 minutes.

Long-Term Follow-Up:

After the End-of-Study visit, you will remain in long-term follow-up until the disease gets
worse, you start a new cancer therapy, or up to two years after the last dose of study drug,
whichever occurs first. During this time, the study staff will call you every 3-6 months and
ask about how you are doing. Each call should last about 5 minutes. If the doctor thinks it
is needed, you may be asked to come to the clinic for a physical exam.

Inclusion Criteria:

1. Male and non-pregnant females >/= 18 years old

2. Subjects must have histologically confirmed malignancy that is metastatic or
unresectable and for which there is no available therapy likely to convey clinical
benefit.

3. Subjects must have received at least one line of systemic therapy in the
advanced/metastatic setting. Subjects with diseases without known effective options
are also eligible. a) Subjects with relapsed and/or refractory lymphoma must have had
at least 2 prior lines of systemic therapy and are not candidates for high dose
therapy/autologous stem cell transplant.

4. Subjects must have evaluable disease for the dose escalation, and measurable disease
for the dose expansion

5. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 to 1.

6. Subjects must have a life expectancy >/= 12 weeks.

7. Subjects must have normal organ and marrow function as defined below: absolute
neutrophil count >/= 1,500/mcL; hemoglobin >/= 9 g/dL; platelets >/= 100,000/mcL;
total bilirubin transaminase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine transaminase
(ALT) serum glutamic pyruvic transaminase (SGPT) institutional ULN in the presence of liver metastases; creatinine clearance >/= 45
mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal.

8. Women of childbearing potential (WOCBP) must agree to use an adequate method of
contraception during the study and until 3 months after the last treatment. Males must
be surgically or biologically sterile or agree to use an adequate method of
contraception during the study until 3 months after the last treatment. Adequate
methods of contraception include: Total abstinence when this is in line with the
preferred and usual lifestyle of the subject; Periodic abstinence (e.g., calendar,
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception;

9. (Incl #8 Cont'd) Female sterilization (have had surgical bilateral oophorectomy with
or without hysterectomy) or tubal ligation at least six weeks before taking study
treatment. In case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment;Male sterilization (at
least 6 months prior to screening). For female subjects on the study, the vasectomized
male partner should be the sole partner for that subject

10. (Incl #8 Cont'd) Combination of any of the two following (a+b or a+c or b+c): a) Use
of oral, injected or implanted hormonal methods of contraception or other forms of
hormonal contraception that have comparable efficacy (failure rate <1%), for example
hormone vaginal ring or transdermal hormone contraception; b) Placement of an
intrauterine device (IUD) or intrauterine system (IUS); c) Barrier methods of
contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with
spermicidal foam/gel/film/cream/ vaginal suppository In case of use of oral
contraception, women should have been stable on the same pill before taking study
treatment.

11. (Incl #8 Cont'd) Note: Oral contraceptives are allowed but should be used in
conjunction with a barrier method of contraception due to unknown effect of drug-drug
interaction. Women are considered post-menopausal and not of child bearing potential
if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at
least six weeks ago. In the case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment is she
considered not of child bearing potential.

12. Subjects must have disease that can be safely biopsied (for RP2D biopsy expansion
cohort only), and agree to undergo a pretreatment and on-treatment biopsy.

13. Subjects with brain metastases must have completed treatment, either surgery or
radiation, 4 weeks or longer prior to screening. A brain magnetic resonance imaging
(MRI) demonstrating there is no current evidence of progressive brain metastases is
required in subjects with previous brain metastasis. Patients with breast tissue
expanders may have brain computerized tomography (CT) for assessment.

14. Subjects must not be on full dose oral anticoagulation such as warfarin. Low dose
warfarin and prophylactic as well as therapeutic low molecular weight heparin are
allowable.

15. Subjects who enroll in the TNBC dose expansion cohort should adhere to the ASCP/CAP
guidelines for the definition of TNBC

16. Subjects must have the ability to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria:

1. Subjects who have had chemotherapy or radiotherapy within 3 weeks (4 weeks for
immunotherapy; 6 weeks for nitrosoureas or mitomycin C) prior to starting the study
agent.

2. Subjects with active brain metastases.

3. Subjects may not be receiving any other investigational agents or have participated in
any other clinical trial involving another investigational agent for treatment of
advanced solid tumors or lymphoma within 3 weeks prior to cycle 1, day 1 of the study.

4. Subjects who had major surgery or radiation therapy within 4 weeks of the first dose
of study drug, except for palliative radiotherapy to a limited field, such as for the
treatment of bone pain or a focally painful tumor mass

5. Subjects with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to IACS-010759.

6. Subjects receiving metformin or other agents known to increase risk of lactic
acidosis.

7. Subjects who previously received IACS-010759 or OXPHOS inhibitors.

8. Subjects with uncontrolled intercurrent illness including, but not limited to ongoing
or active serious bacterial, fungal or viral infection or psychiatric illness/social
situations that would limit compliance with study requirements.

9. Subjects with a history of significant cardiac disease including: Congestive heart
failure requiring therapy; History of myocardial infarction (MI), angina pectoris,
coronary artery bypass graft (CABG) within 6 months prior to starting study treatment;
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete
left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type
II and third degree AV block); Left ventricular ejection fraction (LVEF) <50%
evaluated by echocardiogram (ECHO) or multigated acquisition scan (MUGA); Increased
QTcF (>450 for men and >470 for women)

10. Women who are breast-feeding or pregnant as evidenced by positive serum or urine
pregnancy test performed within 72 hours of first dosing. (Pregnant women are excluded
from this study because it is not known whether IACS-010759 has the potential for
teratogenic or abortifacient effects. Because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
IACS-010759 breastfeeding should be discontinued if the mother is treated with
IACS-010759.)

11. Subjects with significant gastrointestinal abnormalities that may affect absorption
(e.g., gastric bypass, short gut syndrome).

12. Subjects with known human immunodeficiency virus (HIV), acute chronic hepatitis B
virus surface antigen (HBsAg) or hepatitis C virus. (HIV-positive subjects are
ineligible because of the potential for pharmacokinetic interactions of antiviral
therapy with IACS-010759.)

13. Lactic acid levels > 2 mmol/L and/or serum pH <7.35 at baseline.

14. Subjects with other active malignancy in the past 3 years with the exception of
adequately treated basal cell or squamous cell carcinoma of the skin, in situ cervical
cancer, or another early stage cancer that in the discretion of the investigator(s) is
currently in complete remission.

15. Subjects with >/= Common Terminology Criteria for Advance Events (CTCAE) grade 2
toxicity (except alopecia) due to prior cancer therapy.

16. Subjects with any concomitant disease or condition that, in the clinical judgment of
the treating physician, is likely to prevent the subject from complying with any
aspect of the protocol or that may put the subject at unacceptable risk.

17. Subjects with >/= grade 1 peripheral neuropathy at screening.
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