Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Vorinostat

Ixazomib

Histone Deacetylase Inhibitors

Enzyme Inhibitors

HIV Protease Inhibitors

Protease Inhibitors

Dose Escalation Phase: Starting Dose of MLN9708 3 mg by mouth on day 1, 8 and 15. Starting Dose of Vorinostat: 100 mg by mouth twice a day, total of 200 mg/day Days 1 to 21.

Dose Expansion Phase Starting Doses of MLN9708 and Vorinostat: Maximum tolerated dose from Dose Escalation Phase.

Dose Escalation Phase - Starting Dose of MLN9708: 3 mg by mouth on day 1, 8 and 15.

Dose Expansion Phase Starting Dose of MLN9708: Maximum tolerated dose from Dose Escalation Phase.

MLN9708

Dose Escalation Phase - Starting Dose of Vorinostat: 100 mg by mouth twice a day, total of 200 mg/day Days 1 to 21.

Dose Expansion Phase Starting Dose of Vorinostat: Maximum tolerated dose from Dose Escalation Phase.

Siqing Fu, MD,PHD

The goal of this clinical research study is to find the highest tolerable dose of the combination of MLN9708 and vorinostat that can be given to patients with advanced solid tumors. The safety of these drugs will also be studied.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose level of MLN9708 and vorinostat based on when you join this study. Up to 4 dose levels of the MLN9708 and vorinostat combination will be tested. Up to 6 participants will be enrolled at each dose level combination. The first group of participants will receive the lowest dose level combination. Each new group will receive a higher dose of either MLN9708 or vorinostat than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose combination of MLN9708 and vorinostat is found or all 4 dose levels are filled. Up to an additional 14 participants will be enrolled in the highest dose level of the study drug combination.

The dose of the study drug combination that you receive may be lowered if you have intolerable side effects.

Study Drug Administration:

Each study cycle is 28 days.

You will take MLN9708 capsules by mouth every 7 days (on Days 1, 8, and 15 of every cycle). You should swallow MLN9708 capsules whole with 8 ounces (1 cup) of water. Each capsule should be swallowed separately with a sip of water. Do not break, chew, or open the capsules. Each dose should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal. If you miss a dose, take it as soon as you remember, as long as the next scheduled dose is at least 72 hours (3 days) away. You should not take a double dose to make up for a missed dose. If you vomit after taking a dose, wait until the next scheduled dose. Do not take an additional dose.

You will take vorinostat capsules by mouth on Days 1-21 of each cycle, followed by a break of 7 days. You should swallow vorinostat capsules whole with water. Do not break, chew, or open the capsules. Vorinostat should be taken with food. If you miss a dose, take it as soon as you remember, as long as the next scheduled dose is at least 12 hours away. You should not take a double dose to make up for a missed dose. If you vomit after taking a dose, wait until the next scheduled dose. Do not take an additional dose.

It is important that you tell your doctor if you have any side effects while on this study. If you have side effects or abnormal test results, you may be asked to return to the clinic for more tests until the side effects or abnormal test results improve. Your dose of study drug may be changed and/or you may be given drugs to help control the side effects.

Study Visits:

One (1) time each week during Cycle 1:

° Blood (about 6 teaspoons) will be drawn for routine tests and to check your liver and kidney function.

On Day 1 of Cycles 2 and beyond:

* You will have a physical exam.
* Blood (about 6 teaspoons) will be drawn for routine tests.
* If your doctor thinks it is needed, urine will be collected for routine tests.

At the end of Cycles 2 and beyond:

* You will have a CT, PET, and/or MRI scan to check the status of the disease. If your doctor thinks it is needed, you may have measurement sooner.
* If the study doctor thinks it is needed, blood (about 1 teaspoon) will be drawn to measure tumor markers. Tumor markers can be used to check the status of the disease.

Any time the doctor thinks it is needed:

* Blood (about 6 teaspoons) will be drawn for routine tests.
* If you can become pregnant, blood (about 1 teaspoon) will be collected for a pregnancy test.
* You will have an EKG to check your heart function.

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 study drug if the disease gets worse, if intolerable side effects occur, if you develop new health problems, or if you are no longer able to follow study directions.

You may choose to stop taking the study drugs at any time. You should tell the study doctor right away if you are thinking about no longer taking part in this study. The study doctor will talk to you about how to safely stop taking the study drugs.

Your participation on the study will be over after the end-of-study visit.

End of Study Visit:

Within 30 days after your last dose of the study drugs, the following tests and procedures will be performed:

* You will have a physical exam.
* Blood (about 7 teaspoons) will be drawn for routine tests, tests of your kidney and liver function, and tumor marker testing.
* You will have a CT, PET, and/or MRI scan to check the status of the disease. If your doctor thinks it is needed, you may have a scan performed sooner.

This is an investigational study. MLN9708 is not FDA approved or commercially available. MLN9708 is currently being used for research purposes only. Vorinostat is FDA approved and commercially available to treat advanced cutaneous T-cell lymphoma.

The study doctor can explain how the study drugs are designed to work.

Up to 56 patients will take part in this study. All will be enrolled at MD Anderson.

MLN9708 and Vorinostat in Patients With Advanced p53 Mutant Malignancies

A Phase I Study of MLN9708 and Vorinostat to Target Autophagy in Patients With Advanced p53 Mutant Malignancies

Maximum tolerated dose is the highest dose level in which 6 patients have been treated with at most 1 experiencing dose limiting toxicity (DLT). Dose-limiting toxicity defined if the events occur within the first cycle (28 days).

Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by RECIST criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a ≥ 25% decrease in CA125 for patients with ovarian cancer), or (4) a partial response according to the Choi criteria96-98, i.e. decrease in size by 10% or more, or a decrease in tumor density, as measured by Hounsfield units (HU), by more than or equal to 15%.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
MLN9708 and Vorinostat in Patients With Advanced p53 Mutant Malignancies	NCT02042989	Advanced Cancer...	MLN9708 Vorinostat	18 Years -	M.D. Anderson Cancer Center
MLN9708 and Vorinostat in Patients With Advanced p53 Mutant Malignancies	NCT02042989	Advanced Cancer...	MLN9708 Vorinostat	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for advanced p53 mutant malignancies