Clinical Trials

Study : NANT 2007-03

Vorinostat and MIBG in Recurrent or Resistant Neuroblastoma Patients

Protocol Title: Vorinostat With 131I-MIBG Therapy for Resistant/Relapsed Neuroblastoma: A Phase 1 Study (IND# 105, 744)

Study Chair: Steven DuBois, MD. (University of California, San Francisco School of Medicine)

What is this study about:

This study will combine an oral drug called vorinostat with an intravenous agent called metaiodobenzylguanidine (MIBG) that can be used to deliver radiation to neuroblastoma tumors.

Vorinostat is a drug that is FDA-approved to treat a certain type of cancer mainly seen in adults. Vorinostat affects the way the DNA that carries our genes is folded in cells. In the laboratory, vorinostat causes neuroblastoma cells to stop growing. This effect is even greater when vorinostat is combined with radiation.

MIBG is taken up by neuroblastoma tumor cells. MIBG can be combined together with radioactive iodine (¹³¹I) to form the radioactive compound ¹³¹I-MIBG. The ¹³¹I-MIBG compound delivers radiation to the neuroblastoma cancer cells and causes them to die.

Giving vorinostat together with the ¹³¹I-MIBG may help the ¹³¹I-MIBG to kill more neuroblastoma cells. ¹³¹I-MIBG lowers the number of blood forming cells (called stem cells) in the bone marrow when it is given at higher doses. Since the combination of vorinostat and ¹³¹I-MIBG is expected to increase this effect, all patients will get back their own stem cells to help the bone marrow recover from this therapy.

This study will be the first study to test giving vorinostat together with ¹³¹I-MIBG and will help determine the highest doses of vorinostat and ¹³¹I-MIBG that can safely be given together to patients with resistant/relapsed neuroblastoma.

Why is this study being done:

To find the highest doses of vorinostat and ¹³¹I-MIBG without causing severe side effects
To find out the side effects seen by giving ¹³¹I-MIBG and vorinostat at different dose levels
To measure the effects of vorinostat on proteins and genetic material in blood cells
To determine if your tumor gets smaller after treatment with ¹³¹I-MIBG and vorinostat.

Criteria that need to be met to participate in this study

Patients must be at least 24 months and no older than 30 years of age when registered on study.
Patients must have relapsed neuroblastoma, refractory neuroblastoma that had less than a partial response to standard treatment or persistent neuroblastoma that had at least a partial response to standard treatment.
Patients who have at least a partial response to standard treatment who still have neuroblastoma that can be seen on CT/MRI or MIBG scans must have a surgical biopsy done of the tumor to confirm that it is neuroblastoma. Patients with relapsed or refractory neuroblastoma do not need to have a biopsy done to enter on study.
Patients must have evidence of MIBG uptake into tumor at one site within 4 weeks prior to entry on study and subsequent to any intervening therapy.
Patients must have a stem cell product available that meets study criteria. If they don't already have stem cells frozen away then they must be able to have a stem cell collection done to collect the necessary amount of stem cells for study entry and these stem cells must meet study criteria.
Patients must have adequate heart, kidney, liver and bone marrow function. Patients who have bone marrow disease must meet the bone marrow function criteria to enter the study.

Patients cannot participate in the study if:

They have had treatment with ¹³¹I-MIBG before.
They have had prior treatment with vorinostat or other HDAC inhibitor.
They have had a stem cell transplant using another person as the stem cell donor. (You can still be in the study if a previous transplant used your own stem cells)
They have other medical problems that could get much worse if they had this treatment.
They are on dialysis for bad kidney function.
They have a history of unexplained blood clot, pulmonary embolus, thrombotic stroke, or arterial clot.
They are pregnant or breast feeding.
They have active infections such as hepatitis or fungal infections.
They had total body radiation or radiation to the entire belly or a large amount of radiation to the liver or kidney (some radiation to the liver or kidneys is ok).
They can't cooperate with the special precautions that are needed during MIBG treatment.

Study Procedures

This study will test up to 3 vorinostat doses and up to four ¹³¹I-MIBG doses in groups of 3-6 patients, which will be assigned upon enrollment. The starting vorinostat dose for the first group of patients is about 20% lower than what is currently being given to patients receiving vorinostat alone without bad side effects. The dose of ¹³¹I-MIBG will then be increased in the second group of patients. If this is tolerated without serious side effects, then the vorinostat dose will be increased ("dose escalation") in groups of 3-6 patients until serious side effects are seen. At that point, investigators will have found the highest dose of vorinostat that can be given along with ¹³¹I-MIBG without bad side effects.

Next, the ¹³¹I-MIBG dose will be increased in groups of 3-6 patients until serious side effects are seen. At that point, investigators will have found the highest doses of both vorinostat and ¹³¹I-MIBG that can be safely given together without bad side effects. An additional six patients will be treated at the highest dose of vorinostat and ¹³¹I-MIBG to learn more about the side effects and the response of the tumor with those doses.

Patients will receive vorinostat by mouth once a day on Days 1-14, and will be started prior to a hospital admission. Vorinostat will be given as a liquid in all patients. ¹³¹I-MIBG will be given in the hospital on Day 3. Patients will get their stem cells back on Day 17 and receive GCSF (Neupogen or filgrastim) until their white blood cells recover.

Patients will be evaluated after finishing this treatment around 2 months after starting.

Patients will only receive this combination of vorinostat and ¹³¹I-MIBG once as part of this study.

This diagram outlines the treatment regime on this study:

(Please click the diagram thumbnail to view a larger version)

Vorinostat	V	Days 1-14
¹³¹I-MIBG	M	Day 3
Stem Cells	HSC	Given on Day 17
GCSF	GCSF	Given after stem cells until white blood count recovers
Evaluation	Eval	Evaluations after finishing treatment on Day 56

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