Conditions: Glioblastoma Multiforme Anaplastic Glioma
Keywords: Glioblastoma Multiforme Anaplastic Glioma Vorinostat Suberoylanilide Hydroxamic Acid SAHA MSK-390 Zolinza Isotretinoin Accutane 13-cis-Retinoic Acid Carboplatin Paraplatin CBT Temozolomide Temodar
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 55
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if vorinostat when given with isotretinoin and temozolomide can help to control glioblastoma or gliosarcoma. The safety of these drug combinations will also be studied.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 3 groups. If you are on of the first 30 participants in the study, you will be randomly assigned to a group. If you are enrolled after the first 30 participants, you will be more likely to be enrolled in the group that is showing better results.

* If you are in Group 1, you will take vorinostat and isotretinoin.
* If you are in Group 2, you will take isotretinoin and temozolomide.
* If you are in Group 3, you will take vorinostat, isotretinoin and temozolomide.

Study Drug Administration:

Each study cycle is 28 days.

You will take vorinostat by mouth once a day during Days 1-7 and Days 15-21 of each cycle. You should take vorinostat by mouth in the morning, at about the same time each day. Vorinostat capsules should be swallowed whole and should not be opened. If a capsule is damaged or broken, spills of powder from vorinostat capsules should be cleaned up carefully. If you come in contact with the powder, you should wash your hands thoroughly. If the spill is on a surface, the area must be washed at least 3 times with rubbing alcohol, followed by water. Vorinostat capsules should be stored at room temperature (59°-86°F \[15°-30°C\]) in a dry area. You should take vorinostat with food, but not a high fat meal.

You will also take isotretinoin by mouth 2 times a day on Days 1-21 of each cycle.

You will take temozolomide by mouth once a day on Days 1-7 and Days 15-21 of each cycle. You should take temozolomide by mouth at bedtime, at about the same time each day. You should swallow the temozolomide capsules whole, one right after the other, without chewing them. They should be taken on an empty stomach (at least 2 hours after eating) with 1 cup (about 8 ounces) of water.

If you vomit while taking vorinostat, isotretinoin and/or temozolomide, you should not "make up" the dose. You should wait until the next scheduled dose.

Study Visits:

At Week 2 of every cycle:

° Blood (about 1 teaspoons) will be drawn for routine tests.

At Week 4 of Cycles 1:

* Blood (about 2 teaspoons) will be drawn for routine tests and to check how well your blood clots,.
* If you are able to become pregnant, you will have a blood (about 1/2 teaspoon) pregnancy test.

At Week 4 of Cycle 2 and then every other cycle after that (Cycles 4, 6, 8, and so on):

* You will have a physical exam, including a neurological exam.
* Blood (about 2 teaspoons) will be collected for routine tests. This routine blood draw will also include a pregnancy test if you can become pregnant.
* Blood (about 2 teaspoons) will be drawn to check how well your blood clots, your pancreas function and the amount of fats in your blood.
* You will have a brain MRI scan to check the status of the disease.

At any time during the study, extra tests may be performed if the doctor thinks they are needed for your safety. The study doctor will tell you more about any extra tests.

Length of Study:

You may take the study drug(s) for up to 1 year. You may continue to receive the study drug(s) beyond 1 year if your doctor decides that it is in your best interest. You will be taken off study early if the disease gets worse or you have intolerable side effects.

Long-Term Follow-Up:

After your last dose of the study drug, every 2 months after that, you may be called and asked how you are feeling. This phone call should take about 5-10 minutes.

If you stop the study drugs because of intolerable side effects, you will visit the clinic every 2 months, unless the disease gets worse. At these visits, You will have a physical exam, including a neurological exam.

* Blood (about 2 teaspoons) will be collected for routine tests. This routine blood draw will also include a pregnancy test if you can become pregnant.
* Blood (about 2 teaspoons) will be drawn to check how well your blood clots, your pancreas function and the amount of fats in your blood.
* You will have a brain MRI scan to check the status of the disease.

This is an investigational study. Isotretinoin, temozolomide, and vorinostat are FDA approved drugs and commercially available. The use of these drugs in this combination is investigational.

Up to 135 patients will take part in this study. Up to 30 will be enrolled at MD Anderson.

Arms:
arm 1: Vorinostat plus isotretinoin arm 2: Temozolomide plus isotretinoin arm 3: Vorinostat plus isotretinoin plus temozolomide arm 4: Non-Surgical arm 5: Surgical Arm

Interventions: intervention 1: Vorinostat intervention 2: Isotretinoin intervention 3: Surgical Resection intervention 4: Temozolomide
Intervention descriptions: intervention 1: Phase I/Arm 1: Level 0 = 300 mg PO x 14 days; Level I = 400 mg PO x 14 days; Level II = 500 mg PO x 14 days.

Phase I/Arm 3: Level -II = 300 mg PO x 14 days; Level -I = 400 mg PO x 14 days; Level 0 = 400 mg PO x 14 days; Level I = 500 mg PO x 14 days. intervention 2: Phase I/Arm 1: Level 0 = 100 mg/m\^2/day PO x 21 days; Level I = 100 mg/m\^2/day PO x 21 days; Level II = 100 mg/m\^2/day PO x 21 days.

Phase I/Arm 2: Level 0 = 100 mg/m\^2/day PO x 21 days; Level I = 100 mg/m\^2/day PO x 21 days; Level II = 100 mg/m\^2/day PO x 21 days.

Phase I/Arm 3: Level -II = 100 mg/m\^2/day PO x 21 days; Level -I = 100 mg/m\^2/day PO x 21 days; Level 0 = 100 mg/m\^2/day PO x 21 days; Level I = 100 mg/m\^2/day PO x 21 days; Level II = 100 mg/m\^2/day PO x 21 days. intervention 3: Surgical Resection for recurrent Glioblastoma Multiforme intervention 4: Phase I/Arm 2: All Levels = 150 mg/m2/day PO X 14 days.

Phase I/Arm 3: Level 0 = 150 mg/m2/day PO X 14 days; Level I = 150 mg/m2/day PO X 14 days; Level -I = 125 mg/m2/day PO X 14 days; Level -II = 125 mg/m2/day PO X 14 days; Level -III = 100 mg/m2/day PO X 14 days.

Protocol document:
Prot_SAP_000.pdf: 
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The University of Texas 
M. D. ANDERSON CANCER CENTER
DEPARTMENT OF NEURO-ONCOLOGY 
DIVISION OF MEDICINE 
Protocol Title: Phase I / II Adaptive Randomized Trial of Vorinostat, Isotretinoin 
and Temozolomide in Adults with Recurrent Glioblastoma Multiforme 
TABLE OF CONTENT: 
1.0 
OBJECTIVES 
2.0 
BACKGROUND 
3.0 
DRUG BACKGROUND 
4.0 
ELIGIBILITY CRITERIA 
5.0 
TREATMENT PLAN 
6.0 
PRE-STUDY EVALUATION 
7.0 
ON-STUDY EVALUATION 
8.0 
RESPONSE CRITERIA 
9.0 
DATA AND SAFETY MONITORING 
10.0 CRITERIA FOR DISCONTINUATION OF TREATMENT 
11.0 STATISTICAL CONSIDERATIONS 
12.0 COMPLIANCE AND DATA MANAGEMENT 
13.0 REFERENCES 
1.0 OBJECTIVES 
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1.1 Phase I 
 
To determine the maximum tolerated dose (MTD) of vorinostat + isotretinoin 
(cRA), temozolomide (TMZ) + cRA, and vorinostat + cRA + TMZ combinations in 
adult patients with recurrent glioblastoma multiforme (GBM) and anaplastic 
gliomas. 
 
1.2 Phase II 
 
Primary endpoint: 
 
1.  To determine the efficacy of vorinostat + cRA, versus TMZ + cRA, versus 
vorinostat + cRA + TMZ in patients with recurrent glioblastoma multiforme as 
determined by Progression Free Survival (PFS)  using an adaptive 
randomization phase II trial design. 
 
Secondary endpoints:  
 
2.  To determine the radiological response, progression free survival at 6 
months, overall survival and unexpected toxicity in the three treatment arms.  
 
3.  To obtain exploratory data regarding histone 3 and 4 acetylation and p21 
levels in tumor tissue and peripheral monocytes in a subset of surgical 
patients and in non-surgical patients with available tissue from prior surgical 
interventions. 
 
4.  To evaluate the occurrence of symptoms and correlate to disease 
progression and tolerance to treatment using the MD Anderson Symptom 
Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. 
 
 
2.0 BACKGROUND 
 
2.1 The Disease  
 
GBMs are the commonest of adult gliomas and are notorious for their intrinsic 
heterogeneity, high morbidity and mortality. Management of these tumors requires 
multimodality treatment with maximum feasible surgery, radiation therapy and in 
some instances chemotherapy. However, despite aggressive measures, median 
survival is about 12-18 months reflecting the grim prognosis of patients with this 
disease. In patients >50 years of age, median survival is dismal with values of 5 - 7 
months from diagnosis. These data have spurred the development of new 
approaches against these tumors that seek to target their biologic behavior.  Several 
novel agents have emerged in the search for effective therapies against these 
malignancies. Most of them have been tried as single agents and several have failed 
to demonstrate statistically significant activity. Some treatments delineate subsets of 
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patients who respond to the therapy, the reasons for which are unclear. A recent 
Phase III trial showed that combining continuous low dose temozolomide (75 
mg/m2/day x 42 days) with conventional radiation therapy followed by standard dose 
temozolomide therapy (200 mg/m2/day x 5 days every 28 days) for 6 months 
significantly prolonged survival in adult patients with GBM [1]. These data have led 
to widespread use of temozolomide as first line therapy for patients with GBM. 
However, when the tumor recurs, there is no established second line therapy that 
has shown benefit. This has generated an area unmet need for which several 
treatment options are currently being explored. 13-cis retinoic acid (cRA) has shown 
activity in this population in early phase II trials [2,3]. However, patients fail this 
treatment possibly because of development of retinoid resistance. Overcoming such 
resistance by use of agents such as vorinostat (SAHA), a histone deacetylase 
(HDAC) inhibitor, could potentially enhance the activity of retinoids against recurrent 
GBM. Additionally, the activity of retinoids in such a setting could also be enhanced 
by the use of cytotoxic agents such as temozolomide. Evidence of the potential 
benefit of such an approach was seen in a phase II trial combining temozolomide 
and cRA against recurrent GBM in which the progression free survival was better 
with the combination compared with historical controls treated with temozolomide 
alone [4]. These data lead us to propose the present study which aims to determine 
the potential of vorinostat + cRA, versus temozolomide + cRA, versus vorinostat + 
cRA + temozolomide, in an attempt to delineate the best combination against 
recurrent GBM. 
 
 
 
2.2 Retinoids 
 
Retinoids, the natural and synthetic derivatives of vitamin A, are clinically active in 
diverse premalignant and malignant conditions, such as acute promyelocytic 
leukemia, cutaneous T-cell lymphomas, leukoplakia, squamous cell carcinomas of 
the skin, and basal cell carcinomas. Although modest activity was observed in a 
randomized phase II trial in head and neck cancer [5], 13-cis-retinoic acid (cRA) has 
limited activity as a single agent in common advanced solid tumors, such as non-
small cell lung, breast and colon cancer.  
 
2.2.1 Retinoids and gliomas  
 
The rationale for the use of retinoids in human gliomas comes from in vitro studies 
demonstrating differentiating and growth inhibitory effects of retinoic acid on glioma 
cells. The in vitro response among various cell lines studies is heterogeneous. The 
growth inhibitory effect in human glioma cells is related to decrease in EGF receptor 
mediated phosphorylation activity. A phase II study was conducted in MDACC to 
determine the efficacy of cRA in patients with recurrent malignant brain tumors [2].  
Forty-three patients were treated with cRA at a starting dose of 80 - 120 mg/m2 per 
day for 3 weeks followed by one week without treatment, then repeated to comprise 
an 8-week course of therapy. Overall, 23 (53%) patients had either response or 
stable disease to this treatment; three (7%) patients had achieved partial response, 
7 (16%) achieved minor response and 13 (30%) patients remained stable. Twenty 
patients had disease progression. The median time to tumor progression for these 
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patients was 16 weeks. Recent data from a second study also supports a role for 
retinoids in treatment of gliomas [3]. A phase II trial utilizing 13 cRA in combination 
with temozolomide in 98 patients with malignant gliomas showed that the 
combination was associated with 43% 6-month progression free survival compared 
with database survival rate of 21% with temozolomide as a single agent [4]. These 
preliminary results suggest that cRA alone or in combination with cytotoxic agents is 
active against malignant gliomas and more studies are warranted. In addition, these 
data suggest a role for retinoids in treatment of gliomas.  
 
2.3 HDAC inhibitors  
 
Chromatin is a highly specialized structure composed of tightly compacted 
chromosomal DNA. Gene expression within the nucleus is controlled, in part, by a 
host of protein complexes which continuously pack and unpack the chromosomal 
DNA from the inaccessible, tightly packed nucleosomal particles (heterochromatin) 
to the accessible, unwound nucleosomal particles (euchromatin). One of the known 
mechanisms of this packing and unpacking process involves the acetylation and 
deacetylation of histone proteins comprising the nucleosomal core.  
 
The enzymes responsible for reversible acetylation-deacetylation of histone proteins 
are histone acetyltransferases (HATs) and histone deacetylases (HDACs), 
respectively. Acetylated histone proteins confer accessibility of the DNA template to 
the transcriptional machinery for expression. HDACs deacetylate histone proteins 
and thus, may act as transcriptional repressors. There is increasing evidence that 
HDAC or HAT activity is altered in many cancers, including gliomas [6]. Inhibitors of 
HDACs induce hyperacetylation of histones that modulate chromatin structure and 
gene expression. These inhibitors  have been shown to inhibit growth, induce 
differentiation, and induce apoptosis of tumor cells in vitro and in vivo, and represent 
a promising therapeutic approach to cancer.  
 
Three classes of HDACs have been identified.  Class I human HDACs (HDAC1, 
HDAC2, HDAC3, HDAC8 and HDAC11) have homology to a yeast HDAC called 
Rpd3.  Class II HDACs include HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and 
HDAC10. Class II HDACs are homologous to the yeast HDAC Hda1. The key 
catalytic residues have been conserved in both the Class I and Class II HDACs. The 
third class of human HDACs consists of homologues of yeast Sir2. The catalytic site 
of this third class is not similar to that of the Class I and Class II enzymes. Class III 
HDACs require nicotinamide-adenine dinucleotide (NAD) for activity.  
  
Several HDAC inhibitors from multiple chemical classes have been developed and 
are currently in clinical trials. Among these, vorinostat (also known as 
suberoylanilide hydroxamic acid, SAHA, MK-0683 or L-001079038) is a potent 
HDAC inhibitor that can be administered orally with excellent bioavailability. 
Vorinostat was synthesized and identified first as a differentiation/apoptosis-inducing 
agent of transformed cells. Studying its mechanism of action led to the discovery of 
its HDAC inhibitory activity. Vorinostat inhibits the activity of both Class I (HDAC1 
and 3) and Class II (HDAC6) HDACs, but does not inhibit the activity of Class III 
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HDACs (hSirT1). 
 
Vorinostat binds directly to the catalytic pocket of HDAC enzymes. The ability of 
vorinostat to inhibit HDAC activity has been assessed in vitro using affinity purified 
HDAC1. The anti-neoplastic effect of vorinostat is attributed to the inhibition of 
HDAC activity and subsequent accumulation of acetylated histones, leading to the 
activation of genes whose expression causes induction of differentiation or apoptosis 
and the inhibition of tumor growth. Vorinostat causes G1 or G2 phase cell-cycle 
arrest, apoptosis, or differentiation in cultured transformed cells. The activity of 
vorinostat was investigated using the 60 cell line screen at National Cancer Institute 
(NCI) and IC50. Values ranging from approximately 500 nM to 5 μM were observed 
for growth inhibition activity of vorinostat. Vorinostat has also been shown to have 
synergetic and additive activity in combination with other cancer therapies (including 
radiation, kinase inhibitors, cytotoxic agents, and differentiating agents) in a variety 
of cultured human transformed cell lines [7]. 
 
2.3.1 HDAC inhibitors and gliomas  
 
HDAC inhibitors have shown preclinical inhibition of glioma cell lines in vitro and in 
vivo. In particular, vorinostat upregulates p21, decreases VEGF levels and increases 
apoptosis in various glioma cell lines. Also, in vivo glioma xenograft studies 
demonstrate an increased survival time in rats treated with vorinostat. Other HDAC 
inhibitors, such as trichostatin A, FK228 and sodium butyrate, show similar effects in 
vitro. Ongoing clinical studies are testing anti-tumor activity of vorinostat either as a 
single agent or in combination with temozolomide in gliomas. 
 
2.3.2 Preclinical experience with vorinostat  
 
Vorinostat has been demonstrated to have biological and anti-neoplastic activity in 
murine and human xenograft models. Intraperitoneal administration of vorinostat 
causes significant tumor growth inhibition in human prostate cancer xenografts in 
mice; tumor regressions were observed at vorinostat doses (50 mg/kg/day) that did 
not produce toxic side effects. Intraperitoneal administration of vorinostat in 
combination with retinoic acid induced leukemic remission and prolonged survival in 
a therapy-resistant transgenic mouse model of acute promyelocytic leukemia (APL). 
Vorinostat administered to carcinogen-treated rats in feed over a period of 130 days 
increased tumor latency and reduced mammary tumor incidence, multiplicity, and 
volume. Vorinostat administered in feed for 5 weeks also inhibited growth of 
established rat mammary tumors. Vorinostat administered to carcinogen-treated 
mice in feed over a period of 18 weeks reduced lung tumor multiplicity. 
Intraperitoneal administration of vorinostat causes significant tumor growth inhibition 
in both human breast carcinoma and human colon carcinoma cancer xenografts in 
mice. Tumor growth inhibition was observed at vorinostat doses (100 mg/kg/day) 
that do not produce toxic side effects. 
 
2.3.3 Pharmacokinetics and toxicity  
 
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The pharmacokinetics and toxicokinetics of vorinostat have been evaluated in mice, 
rats, dogs and humans. Rapid oral absorption has been noted in all species studied. 
Vorinostat (0.5 to 50 μg/mL) exhibited moderate reversible binding to plasma 
proteins. In human plasma, vorinostat appears to bind primarily to human serum 
albumin; however, some binding of vorinostat was also observed in solutions of α1-
acid glycoprotein. 
 
Vorinostat was excreted exclusively as metabolites, the major of which were largely 
attributed to glucuronidation and hydrolysis followed by β-oxidation pathways. 
 
Although pharmacokinetic studies are still ongoing, oral vorinostat is able to inhibit 
histone deacetylases (target enzymes) in peripheral mononuclear cells at all oral 
doses starting with the 100 mg dose level. At higher dose levels of 400 mg and 600 
mg, duration of target enzyme inhibition lasted at least 10 hours. 
 
The major pathways of metabolism of vorinostat involve glucuronidation and 
hydrolysis followed by β-oxidation. As vorinostat is not eliminated via cytochrome 
P450 pathways, it is anticipated that vorinostat will not to be subject to drug-drug 
interactions when co-administered with drugs that are known to be CYP inhibitors. 
Although vorinostat was not a potent reversible inhibitor of the cytochrome P450 
isozymes (IC50 >75 μM), gene expression studies detected some potential for 
suppression of CYP2C9 and CYP3A4 activities at ≥10 μM vorinostat; however, 
these changes were observed at concentrations higher than the pharmacologically 
relevant serum concentration of 2 μM (Cmax). 
 
The main toxicities observed in animal models were weight loss and loss of appetite, 
apparent hemolytic anemia (rats only at 3.8 times the equivalent 400 mg human 
dose), leukopenia (rats only at 1.3 times the equivalent 400 mg human dose), 
thrombocytopenia (male rats only, statistically significant change at 0.5 times the 
equivalent 400 mg human dose but within normal range at all doses), and 
gastrointestinal tract irritation (dogs only, at 8.5 times the equivalent 400 mg human 
dose). Although statistically significant and dose-dependent, many of the clinical 
pathology findings were within normal historical ranges indicating that they that 
should not have major toxicological consequences. The toxicities appeared to be 
rapidly reversible within 12 to 14 days. There has been no evidence of cardiac 
toxicity based on electrocardiogram (ECG, dogs only), blood pressure (dogs only), 
heart rate (dogs only), creatinine kinase, organ weight, gross pathology, or 
histopathology assessments in studies up to one month duration. No serious, 
irreversible damage to any vital organ has been observed. Importantly, toxicities in 
rats and dogs were predictive of adverse effects in humans (anorexia, weight loss, 
fatigue). Toxicities present in animals would be manageable in the clinic, and the 
onset of serious toxicity is readily forecast by prodromal symptoms. The nonclinical 
toxicity profile of vorinostat is acceptable for an oncology drug. 
 
Vorinostat was evaluated in a panel of genetic toxicity assays; in vivo and in vitro 
assays were found to be positive. Therefore, vorinostat should not be taken by 
pregnant women. Pregnancy should be avoided both in female subjects taking 
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vorinostat, and as data are not yet available to establish the safety of vorinostat 
ingestion in male patients who impregnate their partners, and in female partners of 
male subjects taking vorinostat for at least 30 days after last dose of vorinostat. 
 
2.3.4 Clinical experience with vorinostat  
 
As of 24-Oct-2005, 17 Merck, Sharp and Dohme, Corp.,. sponsored clinical trials 
and 3 Investigator sponsored studies have been initiated with vorinostat [7]. Over 
305 patients with advanced malignancies have been treated with vorinostat alone or 
in combination with other chemotherapeutics. In addition, 29 studies with vorinostat 
are ongoing, sponsored by the United States National Cancer Institute (NCI) under 
the Cancer Therapy Evaluation Program (CTEP) with 144 enrolled patients. 
Therefore, over 449 patients have received at least one dose of vorinostat and 
additional studies are planned. 
 
2.3.4.1 Safety and Toxicity  
 
The total daily oral dose of vorinostat administered in these studies ranges from 200 
mg to 900 mg. The tolerability of oral vorinostat appears to be determined by total 
daily dose and the length of consecutive days of dosing. The maximum tolerated 
dose (MTD) for continuous daily dosing without a rest period is 400 mg once a day 
or 200 mg twice a day (200 mg b.i.d.). The MTD for intermittent dosing is 300 mg 
b.i.d. x 3 consecutive days per week or 250 mg t.i.d. x 14 consecutive days followed 
by a 7-day rest. Dose-limiting toxicities (DLTs) are mainly non-hematologic (asthenia 
and 
weight 
loss). 
Hematologic 
toxicities 
were 
primarily 
anemia 
and 
thrombocytopenia, most of which were mild to moderate in intensity. The majority of 
DLTs occurred within the first month on oral vorinostat. At continuous daily dosing of 
600 mg once daily, 300 mg b.i.d., and 400 mg b.i.d. that exceeded the MTD, the 
pattern and severity of DLTs were similar. The DLTs were manageable because 
these toxicities resolved quickly after drug administration was interrupted. The 
optimal dose, dose frequency, and dose duration remains under active investigation. 
 
The types of adverse experiences seen in clinical trials of vorinostat were those 
usually associated with chemotherapy, such as fatigue, nausea, vomiting, 
cytopenias, etc. No new or unique adverse experiences were commonly observed. 
The three major clinical categories of adverse experiences attributable to vorinostat 
include a constellation of gastrointestinal symptoms, constitutional complaints, and 
cytopenias. However, most of the adverse experiences were manageable. In fact, 
most of the very common adverse experiences were reversible and could be 
managed using conventional supportive care for chemotherapy. On the whole, 
treatment with oral vorinostat was well tolerated for use in the outpatient setting. 
 
Adverse experiences considered by the Investigators to be at least possibly related 
to vorinostat reported as of 24-Oct-2005 by ≥10% of patients across all Merck, 
Sharp and Dohme, Corp.,. sponsored vorinostat clinical studies are summarized 
below by medical dictionary for regulatory activities (MedDRA), system organ class 
(SOC) and preferred term: 
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SOC 
 
Reported 
Possible 
Related 
Adverse 
Experiences 
in ≥10 % Overall Patients 
Blood and Lymphatic System 
Disorders 
Thrombocytopenia, anemia 
Gastrointestinal disorders 
Nausea diarrhea, vomiting, constipation, dry 
mouth 
General disorders and Administration 
Site Conditions 
Fatigue, pyrexia, chills, edema peripheral 
Investigations 
Blood creatinine increased, weight decreased, 
hemoglobin 
decreased, 
aspartate 
aminotransferase increased, platelet count 
increased, 
prothrombin 
time 
prolonged, 
alanine aminotransferase increase 
Metabolism and Nutritional Disorders 
Anorexia, hyperglycemia 
Musculoskeletal, and Connective 
Tissue Disorders 
Muscle spasm 
Nervous System Disorders 
Dizziness, dysgeusia 
Respiratory, Thoracic and 
Mediastinal Disorders 
 
Cough, dyspnea 
Skin 
and 
Subcutaneous 
Tissue 
Disorders 
Alopecia 
 
 
Certain classes of patients were excluded from the clinical studies conducted to 
date, i.e., patients with significant hepatic or renal impairment or other major medical 
conditions that could have interfered with evaluation of study drug. In addition, 
patients who were pregnant or nursing were excluded from these studies. No formal 
studies evaluating the effect of age, gender, race or organ function (such as liver, 
kidney) on the pharmacokinetics and pharmacodynamics of vorinostat have been 
conducted. Accordingly, there are no clinical data for these populations. 
 
Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) 
were observed infrequently in patients receiving vorinostat concomitantly with 
coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR 
in patients concurrently administered vorinostat and coumarin derivatives. 
 
Vorinostat should not be administered concomitantly with other HDAC inhibitors 
(e.g., valproic acid) as class-specific adverse reactions may be additive. Severe 
(Grade 4) thrombocytopenia with associated gastrointestinal bleeding and anemia 
has been reported with the concomitant use of vorinostat and valproic acid. 
 
2.3.4.2 Efficacy  
 
Although demonstration of efficacy was not a primary objective in Phase I clinical 
studies of vorinostat, preliminary anti-tumor activity was observed in patients with 
acute myeloid leukemia (AML), advanced multiple myeloma, lymphoma, laryngeal 
carcinoma, thyroid carcinoma, and mesothelioma. Similarly, significant anti-tumor 
activity was also observed in the Phase II clinical studies of vorinostat in patients 
with advanced cutaneous T-cell lymphoma (CTCL). 
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Preliminary observations of anti-tumor response in leukemia, lymphoma, myeloma, 
mesothelioma, laryngeal carcinoma and stable disease in thyroid carcinoma require 
confirmation in phase II and III trials. The initial trials of vorinostat activity in 
combinations with other anti-tumor medications are ongoing. 
 
2.4 Temozolomide and gliomas  
 
Temozolomide, an oral alkylating agent with good penetration of the central nervous 
system, has been evaluated in patients with glial malignancies.  Initial studies 
evaluated the efficacy of temozolomide in patients with recurrent glioblastoma and 
anaplastic glioma.  A large, randomized phase II study by Yung and colleagues 
treated patients with recurrent glioblastoma with either temozolomide (200 mg/m2 
days 1-5 of a 28-day cycle) or procarbazine (150 mg/m2 28 day-on, 28-day off 
schedule) (Yung, Albright et al. 2000).  The study demonstrated only a modest 
objective response rate for both regimens (approximately 5%), but a superior 6-
month progression-free survival rate for temozolomide (21% vs. 9%) was found. In 
the pre-radiation setting, a phase II study demonstrated a good objective response 
rate (complete plus partial response = 41%) in patients with glioblastoma during the 
four monthly cycles of treatment, using 200 mg/m2 on days 1 to 5 of a 28-day cycle. 
However, the responses were not durable in many cases and the median 
progression-free survival rate was 3.8 months.  Overall survival for patients on this 
study was 13.1 months, similar to most reports of treatment in newly diagnosed 
patients.  This suggests that the neoadjuvant temozolomide chemotherapy likely had 
little overall benefit.  However, these results did demonstrate definite activity of 
temozolomide for glioblastoma.(Gilbert, Friedman et al. 2002) 
  
Stupp and colleagues performed a phase III trial in patients with newly diagnosed 
glioblastoma, administering a daily lower dose (75 mg/m2) of temozolomide every 
day during the course of radiation therapy, followed by 6 months of adjuvant 
chemotherapy at the standard single-agent dose of 200 mg/m2 for days 1 to 5 of a 
28-day cycle.(Stupp, Mason et al. 2005)  This study, performed by the EORTC and 
the NCIC, randomized patients with newly diagnosed glioblastoma to receive either 
radiation therapy alone or concurrent radiation and temozolomide followed by 6 
months of adjuvant temozolomide.  The study demonstrated a statistically significant 
improvement in median survival for the combination treatment arm (12.1 vs. 14.6 
months) as well as a significant increase in 2-year survival (10% vs 26%). Eighty-
eight percent of the patients received the full course of concurrent temozolomide 
with radiation.  Approximately 40% of patients received the full 6 cycles of 
temozolomide after the completion of the radiation (adjuvant therapy).  Tumor 
progression was the most prominent cause of treatment cessation.  The 
chemoradiation treatment was well tolerated, with an incidence of grade 3 or 4 
hematologic toxicity of < 4%.  This chemoradiation regimen has been widely 
accepted as the new standard of care for patients with newly diagnosed 
glioblastoma.  
 
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As described above, incorporation of a dose-dense strategy for recurrent primary 
brain tumors is supported by the results of a recently reported clinical trial that 
treated patients with recurrent malignant glioma with the week on/week off dosing 
schedule of temozolomide at a dose of 150 mg/m2 /day.  This study reported a 6-
month progression free survival rate of 46%, which compares favorably with the 6-
month PFS rate of 21% reported with conventional 5 day of a 28 day cycle of 
temozolomide (Yung, Albright et al. 2000; Wick, Felsberg et al. 2007).  
 In this study, we will use this schedule to test if combining temozolomide with 
vorinostat and retinoids can enhance the activity of the agent against recurrent 
GBMs.  
 
 
2.5 Rationale for combining retinoids and HDAC inhibitors  
 
At the molecular level, the biologic effects of retinoids are modulated through nuclear 
receptors (named RXRs and RARs). The activated nuclear receptors control the 
expression of genes that mediate retinoid effects, including induction of cell 
differentiation, inhibition of proliferation by cell cycle arrest, and induction of 
apoptosis. Retinoid receptors behave as ligand-dependent transcriptional regulators, 
repressing transcription in the absence of ligand and activating transcription in its 
presence. The different effects on transcription are carried out through recruitment of 
co-regulators: unliganded receptors bind corepressors (NCoR and SMRT) that are 
found within a complex containing histone deacetylase (HDAC) activity, whereas 
liganded receptors recruit coactivators with histone acetylase activity (HATs).  
 
 
The mechanisms of retinoid resistance are not well known [23]. Several mechanisms 
have been proposed, including pharmacologic mechanisms (acceleration of 
metabolism and decreasing plasma levels), and molecular mechanisms (structural 
mutations in the retinoid receptor, altered associations with corepressor molecules). 
Retinoid resistance seems to include increased binding of corepressor/HDAC 
complexes. Thus, HDAC inhibition may counteract the effect of corepressors, 
causing a DNA conformation that facilitates retinoid-induced gene transcription and 
cell differentiation [24].  
 
2.6 Rationale for combining temozolomide with retinoids and HDAC inhibitors 
 
 We hypothesize that the combination of retinoids with HDAC inhibitors can result in 
overcoming of retinoid resistance. This would be expected to provide a robust 
cytostatic effect which may result in prolonged tumor stabilization. We propose to 
extend this rationale by exploring the potential for a DNA damaging agent such as 
temozolomide to convert the cytostatic effect of the combination to a cytotoxic 
response which may potentiate the effects of all agents used in this protocol. 
Because of non-overlapping toxicities and varied mechanisms of activity of these 
agents, we hypothesize that this strategy will result in a potent effect against GBMs.  
In addition, there is a basis for predicting synergy among these three compounds 
from preclinical and clinical studies  - for example, in preclinical studies, HDAC 
inhibitors such as vorinostat can synergize with temozolomide or carboplatin to 
increase cell death over that achieved by either agent alone (Puduvalli et al and 
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Wen et al, unpublished data).. Also, a phase II study of isotretinoin and 
temozolomide in patients with recurrent GBMs showed an improvement in 6 month 
PFS compared with historical controls treated with temozolomide alone [4], 
suggesting that the combination of DNA damaging agents such as temozolomide, 
and isotretinoin can be active against these tumors. In addition, an ongoing phase I 
study of temozolomide combined with vorinostat has completed enrollment with the 
most recent dose level being 500 mg/day on a days 1-7 and 15-21 day dosing of 
vorinostat and 150 mg/day on days 1-5 of temozolomide on a 28 day schedule. 
Toxicities seen in this trial included fatigue and thrmobocytopenia.  A dose dense 
schedule of temozolomide has not yet been explored but the data from the ongoing 
trial will provide a basis for a limited dose level lead-in trial of this combination as 
proposed in this study. The data presented above also provide support for the 
approach proposed in this study. 
 
2.7 Rationale for Dosing Schedule  
 
Preclinical studies of combination of the HDAC inhibitor vorinostat (SAHA) and cRA 
in glioma cells in vitro show that simultaneous administration of SAHA and cRA was 
more potent in inducing apoptosis compared with the schedules of cRA followed by 
vorinostat or vorinostat  followed by cRA (Puduvalli et al, unpublished data). Hence, 
we have chosen to initiate treatment simultaneously with vorinostat  (days 1-14) and 
cRA (days 1-21) in Arm 1.  For Arm 3 which has temozolomide in addition to cRA 
and vorinostat, we will use a days 1-7 and 15-21 dosing of vorinostat to match with 
temozolomide dosing schedule (also days 1-7 and 15-21) . HDAC inhibition 
increases the expression of apoptosis related genes such as caspase 8 and death 
receptors such as DR5. This may result in the glioma cells being potentially primed 
to apoptosis in the presence of an appropriate cytotoxic signal. We hypothesize that 
the addition of a cytotoxic agent such as temozolomide (known to have activity 
against gliomas) with HDAC inhibition will result in a more robust induction of 
apoptosis, potentially translating into clinical benefit. In vitro studies have shown that 
SAHA can potentiate cisplatin induced apoptosis in glioma cells. Based on these 
data, we propose to administer temozolomide on day 1 -7 and  15-21 of each 28 day 
cycle along with SAHA.      
 
 
2.8 Rationale for study design  
 
To assess the activity of a new treatment regimen, conventional phase II designs 
use either a single arm design compared with historical controls or a randomized 
design with a control arm of standard treatment, if such a standard is identified. For 
patients with recurrent GBMs, there are no extant standards of care. In a paradigm 
such as the one being studied in the proposed trial, testing each combination against 
historical controls would involve three separate trials, a process that will not provide 
timely answers to the question at hand nor allow utilization of resources in an 
efficient manner. To overcome some of these hurdles and test these combinations 
against each other as well as historical controls, this study proposes to utilize a 
bayesian adaptive randomization design, which will pit the three treatment regimens 
against each other. This will result in progressive bias of randomization towards the 
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best of the three regimens in a single trial. The "winner" of these three regimens will 
be considered the best regimen for further testing in a larger trial if it compares 
favorably with historical controls [25, 26, 27].      
 
2.9 Rationale for obtaining exploratory data  
 
The identification of markers that are associated with tumor but not with normal 
tissue has allowed the development of highly-specific targeted therapies with 
promising future for treatment of cancer. Targeted therapies are tailored to 
deregulate the signaling pathways involved in malignant progression. Advances in 
our understanding of the molecular changes and resultant cellular effects in 
malignant glioma are expanding the role of targeted therapies for treatment of these 
tumors. However, due to the complexity of the signaling pathways in gliomas and the 
inter- and intratumoral heterogeneity of the disease, only a small proportion of 
patients obtains clinical benefit from these therapies. Further analysis of the 
signaling pathways in tumor tissue before and after treatment may help to delineate 
the subset of patients for which these targeted therapies would be of more benefit 
[28]. For this purpose, we propose to determine the effect of vorinostat on brain 
tumor tissue by directly assessing the effect of the agent on histone acetylation in 
tumor specimens. To do this, we will include in our study 10 patients among those 
recruited for the Phase II trial who have been offered surgical resection of their 
recurrent tumors because of clinical indications, and who consent to taking 
vorinostat for 3 days prior to tumor resection, with the last dose to be given on the 
morning of surgery (see 5.2.2). One important goal of this translational study is to 
demonstrate that vorinostat can inhibit HDAC activity and cause histone 
hyperacetylation in tumor tissue. Histone H3 and H4 acetylation in response to 
vorinostat at a dose of 200 mg in PBMCs is transient and lasts for 4-6 hours. 
Preliminary data suggest that the duration of hyperacetylation may be prolonged to 
8-10 hours if a dose of 400 mg is used. Thus, the dose of the agent and the timing of 
tissue acquisition and processing will be important determinants for demonstrating 
the effects of vorinostat on histone acetylation. While we recognize that the 
biological effects of vorinostat may occur beyond the period of changes in histones, 
the demonstration of histone hyperactylation is proof of principle of primary target 
modulation by the agent. Treatment of patients for 3 days (72 h) prior to surgery also 
allows us to assess the late changes induced by vorinostat such as increased levels 
of p21 or reduction of cyclin B1.  Tissue obtained at surgery will be studied for these 
effects by immunohistochemistry. Other markers of interest in this context including 
cell cycle regulatory molecules and apoptosis markers will also be assessed. Non-
surgical patients will be asked to participate in this component of the trial provided 
that tumor tissue is available from prior surgical interventions. In these patients, we 
will determine the baseline acetylation and p21 levels in tumor tissue and peripheral 
monocytes. Treatment-related changes in peripheral monocytes after vorinostat 
administration will be determined as a surrogate of vorinostat  effect in tumor tissue. 
We will also test the same markers in a group of archived tumor tissue from age and 
relapse-number matched recurrent glioblastoma multiforme patients. 
 
2.10 Rationale for Symptom Assessment Evaluation  
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Glioblastoma multiforme is a highly malignant type of tumor with recognized impact 
on the patients’ physical, and neurologic function [29]. Most patients do succumb to 
their illness within two years. This study seeks to improve on these clinical results, 
hypothesizing that using a combination of cytotoxic and cytostatic agents will result 
in improved survival. However, given the intensive nature of this regimen, it will be 
important to determine whether any survival benefit is associated with an 
improvement in symptoms or is the increase in survival offset by a worsening of 
these parameters. Precedence for measuring “non-therapeutic” endpoints exists in 
oncology research. For example, Gemcitabine was approved by the FDA partially as 
a consequence of the decrease in pain reported in pancreatic patients who were 
treated, not on the basis of survival improvement which was modest, at best [30]. 
There have been efforts in neuro-oncology to evaluate secondary endpoints using 
validated instruments as an additional indicator of benefit.   
 
The M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) allows the 
self reporting of symptom severity and interference with daily activities. It has 
demonstrated reliability and validity in the primary brain tumor patient population 
[31]. This tool represents a modification of the widely used and validated MDASI, 
with particular attention to symptoms common in patients with brain tumors. The 
availability of validated instruments provides an opportunity to prospectively assess 
the impact of treatment, both positive and negative, on patients. This evaluation of 
symptom burden in this study will assist in finding the best possible treatment with 
the least toxicity.     
          
2.11 Preliminary Data from recently completed Phase I trial of vorinostat, 
isotretinoin and Carboplatin 
             
  
The proposed trial is a modification of an existing single institution IRB approved trial 
that is ongoing in MDACC. In the original phase I portion of this trial, we had 
proposed to test the tolerability and efficacy of the combination of vorinostat, 
isotretinoin and carboplatin.   An MTD was established for the combination of 
vorinostat (400 mg/day on days 1-14) and isotretinoin (100 mg/m2/day on days 1-
21) on a 28 day schedule (Arm 1).  Similarly, the MTD for the combination of 
carboplatin (AUC 5 on day 1) and isotretinoin (100 mg/m2/day on days 1-21) has 
also been established (Arm 2). However, when the test combination of vorinostat, 
isotretinoin and carboplatin were combined in a three drug regimen (Arm 3), the 
starting dose level and two lower dose levels (dose levels 0, -1 and -2) proved 
intolerable; this required amending the protocol to introduce a third lower dose level 
(level - 3) which has currently accrued three patients. A dose level below this is not 
considered of interest for this tumor type. The overlapping toxicity of carboplatin and 
vorinostat appears to be the primary reason for the intolerance of this regimen; 
hence, we propose to explore temozolomide as an alternative cytotoxic agent to 
carboplatin which has known activity against malignant gliomas and is currently 
being tested in combination with vorinostat in the upfront setting. The DSMB has 
been notified of these results and we have received approval for holding accrual until 
the current amendment is instituted after IRB review.  
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3.0 DRUG BACKGROUND 
 
3.1 Isotretinoin (13-cis retinoic Acid, cRA)   
 
3.1.1 Therapeutic Classification  
 
Retinoid. 
 
3.1.2 Pharmacologic Data  
 
Isotretinoin is absorbed from the gastrointestinal tract. Due to its high lipophilicity, 
oral absoprtion is enhanced when given with a high-fat meal. Minimal systemic 
absorption occurs following topical application. Peak plasma concentrations occur 1 
to 4 hours after oral doses. Oral bioavailability is low, possibly due to metabolism in 
the gut wall and first-pass metabolism in the liver. Isotretinoin is highly bound to 
plasma proteins (99.9%), primarily albumin. It is metabolized in the liver to its major 
metabolite 4-oxo-isotretinoin; there is also some isomerisation of isotretinoin to 
tretinoin. Isotretinoin, tretinoin, and their metabolites undergo enterohepatic 
recycling. The terminal elimination half-life of isotretinoin is 10 to 20 hours, while that 
of the 4-oxo metabolite may be up to 50 hours; return to physiological levels of 
retinoids takes about 2 weeks after stopping therapy. Equal amounts of a dose 
appear in the feces, mainly as unchanged drug, and in the urine as metabolites.  
 
3.1.3 Pharmaceutical Data  
13-cis-Retinoic acid (cRA) is a synthetic analogue of vitamin A. Chemical name: 
(13Z)-15-Apo- beta- caroten-15-oic acid; (2Z,4E, 6E,8E)-3,7-Dimethyl -9-(2,6,6-
trimethyl cyclohex-1-enyl) nona-2,4,6,8- tetraenoic acid.  It is a yellow to orange 
crystalline powder with a molecular weight of 300.44. Isotretinoin is practically 
insoluble in water; sparingly soluble in alcohol, in isopropyl alcohol, and in macrogol 
400; soluble in chloroform.  
 
3.1.4 Usual Dosage Range  
 
Isotretinoin is FDA approved for treatment of severe acne. Isotretinoin inhibits 
sebaceous gland function and keratinization in pharmacological dosages of 0.5 to 
1.0 mg/Kg/day. Isotretinoin has been used in doses up to 100 mg/m2 daily in divided 
doses for 21 consecutive days, followed by 7 drug-free days for the treatment of 
recurrent malignant gliomas [2,3].  
 
3.1.5 Route of Administration  
 
Oral.  
 
3.1.6 Supplied  
 
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Isotretinoin is commercially available. ACCUTANE®  is available in 10, 20 and 40 
mg soft gelatin capsules for oral administration. Patients, prescribers, pharmacies 
and wholesalers must be registered with the iPLEDGE program. This is a computer-
based risk management program designed to eliminate fetal exposure to isotretinoin 
through a special restricted distribution program approved by the FDA. The 
iPLEDGE program requires that all patients meet qualification criteria and monthly 
program requirements (see 4.17, 6.4, and Appendix I).  
 
3.1.7 Side Effects and Toxicities  
Common side effects include arthralgias, back pain, cheilitis, conjunctivits, dry/itchy 
skin, dry mouth and epistaxis. Serious side effects include birth defects, depression, 
psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive 
and/or violent behavior; pseudotumor cerebri, anaphylactic reactions, elevated 
triglycerides, pancreatitis, hearing impairment, hepatotoxicity, inflammatory bowel 
disease, neutropenia, rhabdomyolysis, decrease in bone mineral density  and visual 
disturbances.  
 
3.2 Vorinostat (Suberoylanilide Hydroxamic acid, SAHA)   
 
3.2.1 Therapeutic Classification  
 
Histone deacetylase (HDAC) inhibitor, antineoplastic. 
 
3.2.2 Pharmacologic Data  
 
Plasma samples for pharmacokinetics were collected in early dose-ranging studies 
with intravenous and oral vorinostat. Exploratory pharmacokinetic analyses of oral 
vorinostat were conducted in a Phase I trial (Protocol 006). However, the vorinostat 
clinical assay was not validated at the time of these analyses. Single dose, multiple 
dose, and fed/fasted pharmacokinetic data were obtained in Protocol 008 using a 
validated clinical assay. This study was conducted in patients with advanced, 
refractory cancer using the dose of 400 mg once daily. The apparent t½ of vorinostat 
was found to be short, on the order of 1.5 hours. In the individual concentration-time 
profiles (but not the mean profiles), there were distinct secondary peaks (likely due 
to continuing absorption), which contributed to the variability in Tmax (range ~0.5 to 
14 hours). A high-fat meal was associated with a small increase in the extent of 
absorption of vorinostat; the geometric mean ratio for AUC0-∞ and 90% CI were 
1.38 (1.21, 1.57). A high-fat meal was also associated with a modest decrease in the 
rate of absorption. A lag time of at least 15 minutes was observed before detectable 
levels of vorinostat were observed in serum in the fed state in most subjects. 
Additionally, Tmax was modestly delayed (from 1.5 to 4 hours) and Cmax was 
similar. The mean apparent t½ was similar between the fasted and fed states. The 
clinical significance of these small effects is uncertain; however, most of the 
vorinostat studies were conducted in the fed state it is recommended that vorinostat 
be administered with food. 
 
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The pharmacokinetics of the two principal inactive metabolites of vorinostat were 
also evaluated following vorinostat dosing in Protocol 008, (O-glucuronide of 
vorinostat [L-001302381] and 4-anilino-4-oxobutanoic acid [L-000341257]). The 
apparent t½ of the O-glucuronide of vorinostat (~1.8 hours) was similar to that of 
vorinostat while that of the 4-anilino-4-oxobutanoic acid was longer (~6 to 9 hours). 
The mean serum exposures (AUC) of the O-glucuronide and 4-anilino-4-oxobutanoic 
acid metabolites were 3- to 4-fold and 10- to 13-fold higher, respectively, compared 
to that of vorinostat. 
 
In general, the pharmacokinetics of vorinostat upon multiple dose administration is 
qualitatively similar to that following single dose administration. The trough 
concentrations following 8 and 21 days of multiple dosing were generally below the 
limit of quantification, which is consistent with the short apparent t½. The apparent 
t½ was similar following a single dose and following 22 days of repeat 
administration. The geometric mean vorinostat AUC accumulation ratio was 1.21. 
Based on an apparent t½ of 1.5 hours, no accumulation would be expected with 
once daily dosing; however, it is possible that intraindividual variability may have 
contributed to a slightly higher ratio. Because the mechanism of action of HDAC 
inhibitors like vorinostat may involve changes in gene expression that could persist 
well after serum concentrations decline, the low trough concentrations do not predict 
that a once daily regimen would be ineffective. 
 
Pharmacodynamic assessment evaluating histone acetylation in peripheral blood 
mononuclear cells (PBMC) was performed. Inhibition of histone deacetylases (target 
enzymes) was achieved in PBMC at the 200 mg dose level. At higher dose levels of 
400 mg and 600 mg, duration of target enzyme inhibition lasted at least 10 hours. 
 
The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis 
followed by beta-oxidation. As vorinostat is not eliminated via cytochrome P450 
(CYP) pathways, it is anticipated that vorinostat will not to be subject to drug-drug 
interactions when co-administered with drugs that are known to be CYP inhibitors or 
inducers. Vorinostat was not a potent reversible inhibitor of the cytochrome P450 
isozymes (IC50 >75 μM). Gene expression studies detected some potential for 
suppression of CYP2C9 and CYP3A4 activities at ≥ 10 μM vorinostat, however, 
these changes were observed at concentrations higher than the pharmacologically 
relevant serum concentration of 2 μM (Cmax). 
 
3.2.3 Pharmaceutical Data   
 
Chemical name: N-hydroxy-N’-phenyl-octane-1,8-diotic acid diamide; N-hydroxyl-N’-
phenyl (9CI) octanediamide Suberoylanilide hydroxamic acid. It is a white to light 
orange powder.Molecular weight is 264.32. Solubility in water is < 5 mg/mL. 
  
3.2.4 Usual Dosage Range   
 
The total daily dose administered in vorinostat trials ranges from 200 mg to 900 mg. 
The tolerability of oral vorinostat appears to be determined by total daily dose and 
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the length of consecutive days of dosing. The administration frequency across all 
studies included once daily, (QD continuous dosing), twice daily (BID) continuous 
dosing, twice daily discontinuous dosing and three times daily (TID) discontinuous 
dosing. The lowest total daily dose of vorinostat used was 200 mg (once daily) and 
the highest total daily doses were 600 mg (once daily), 800 mg (400 mg twice daily), 
and 900 mg (300 mg three times daily). In Protocols 003, 004, 005, 011, 012, 013, 
014 015, 029, and 030 on a 14 consecutive day, twice daily schedule followed by a 
7-day rest period for each 21-day cycle was tested either alone or in combination 
with other chemotherapeutics. In protocol 003 and 004, a 200 mg twice daily dosage 
on this schedule was tolerable. This was anticipated as a 200 mg twice daily dosage 
was tolerable on a continuous basis in Protocol 006. In Protocols 011 and 013, initial 
dose levels of 400 mg twice daily for 14 consecutive days, followed by a 7 day rest, 
and 300 mg twice daily for 14 consecutive days, followed by a 7 day rest period out 
of 21 days exceeded the MTD due to thrombocytopenia. 
 
The maximum tolerated dose (MTD) was determined based upon dose limiting 
toxicities observed in Protocol 006. The maximum tolerated once daily dose is 400 
mg. The 600 mg once daily dose given continuously was not tolerated. The 
maximum tolerated twice daily dose is 200 mg. The 300 mg twice daily dose given 
continuously was not tolerated. The maximum tolerated three times per day dose is 
200 mg for 14 consecutive days followed by 7 days of rest. The 300 mg dose given 
three times daily on this schedule was not tolerated. The maximum tolerated twice 
daily dose for 3 consecutive days per week is 300 mg. The 400 mg twice daily dose 
on this schedule was not tolerated. 
 
3.2.5 Route of Administration:  Oral. 
 
3.2.6 Supplied  
 
Vorinostat is supplied by Merck and Co., Inc.  Vorinostat is supplied as a white, 
opaque gelatin, size 3 capsule, containing 100 mg of vorinostat. The inactive 
ingredients contained in each capsule are microcrystalline cellulose, sodium 
croscarmellose, and magnesium stearate. The capsules are supplied in HDPE (high-
density polyethylene) bottles. Each bottle contains the protocol specified count of 
vorinostat capsules. The shelf-life of the 100 mg capsule is 2 years. 
Special Handling Requirements: Vorinostat is an anticancer drug. Spills of powder 
from vorinostat capsules due to damaged or broken capsules should be cleaned up 
carefully to minimize inhalation of vorinostat. The affected area must be washed at 
least 3 times with ethyl alcohol, followed by water. Direct contact of the powder in 
vorinostat capsules with the skin or mucous membranes should be avoided. If such 
contact occurs, wash thoroughly. Vorinostat capsules should be stored at room 
temperature (do not store above 30°C) in a dry, limited-access area. Care should be 
taken to maintain acceptable storage temperature. Vorinostat capsules should not 
be opened or crushed and must be administered whole. 
 
3.2.7 Side Effects and Toxicities reported in Preclinical and Clinical Studies of 
Vorinostat (CAEPR version 2.4, June 12, 2006; CIB Version 3.0, June 23, 2006  
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A. Toxicities in Preclinical Studies: The main toxicities observed in animal models 
were weight loss and inappetence, apparent hemolytic anemia (rats only at 3.8 times 
the equivalent 400 mg human dose), leukopenia (rats only at 1.3 times the 
equivalent 400 mg human dose), thrombocytopenia (male rats only, statistically 
significant change at 0.5 times the equivalent 400 mg human dose but within normal 
range at all doses), and gastrointestinal tract irritation (dogs only, at 8.5 times the 
equivalent 400 mg human dose).  Although statistically significant and dose-
dependent, many of the clinical pathology findings were within normal historical 
ranges indicating that they that should not have major toxicological consequences.  
The toxicities appeared to be rapidly reversible within 12 to 14 days.  There has 
been no evidence of cardiac toxicity based on electrocardiogram (ECG, dogs only), 
blood pressure (dogs only), heart rate (dogs only), creatinine kinase, organ weight, 
gross pathology, or histopathology assessments in studies up to one month 
duration.  No serious, irreversible damage to any vital organ has been observed.  
Importantly, toxicities in rats and dogs were predictive of adverse effects in humans 
(anorexia, weight loss, fatigue). 
B. Toxicities in Clinical Trials: Among the 101 patients with solid tumor patients 
treated with vorinostat, the most commonly reported adverse experiences were 
fatigue 
(81.2%), 
nausea 
(70.3%), 
anorexia 
(64.4%), 
vomiting 
(53.5%), 
hyperglycemia (52.5%) diarrhea (40.6%), and blood creatinine increased (40.6%).  
Fatigue, the most commonly reported adverse experience was considered by the 
Investigator to be at least possibly related to study drug for 71 (70.3%) patients with 
an intensity of Grade 3 or higher in 16 (15.8%) patient. Other than fatigue, the most 
commonly reported adverse experiences assessed by the Investigator as at least 
possibly related to vorinostat were nausea (65.3%), anorexia (62.4%), vomiting 
(45.5%), hyperglycemia (41.6%) and blood creatinine increased (37.6.%) and 
diarrhea (34.7%).   
Overall, among the 305 patients with all advanced malignancies treated with 
vorinostat in, the most commonly reported adverse experiences were fatigue 
(68.9%), nausea (60%), diarrhea (55.1%), anorexia (47.9%), and hyperglycemia 
(38.7%). Fatigue, the most commonly reported adverse experience was considered 
by the Investigator to be at least possibly reported to study drug for 192 (63.0%) 
patients with an intensity of Grade 3 or higher for 42(13.8%) patients. Other than 
fatigue, the most commonly reported adverse experiences assessed by the 
Investigator as at least possibly related to vorinostat were nausea (55.4%), anorexia 
(46.2%), diarrhea (49.5%), and hyperglycemia (25.2%). 
As of 30-Nov-2005, of the 305 patients exposed to vorinostat, there were 24 deaths 
reported. Most of these deaths (87.5%) were considered by the Investigator to be 
not drug-related, of which 14 (58.3%) were attributed to progression of underlying 
disease. The remaining 3 deaths (AN1008 and AN1048 in Protocol 001 and AN003 
in Protocol 011) were due to single cases of unknown cause, ischemic stroke, and 
tumor hemorrhage, which were considered by the Investigator to be related to study 
drug. A total of 5 participants in the CTCL trials (3 in the 400-mg daily treatment 
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group) died during the study observation period. Ten solid tumor patients (one in the 
400-mg daily treatment group) and 9 non-CTCL hematologic malignancy patients 
(none in the 400-mg daily treatment group) died during the study observation period.  
 
Likely (>20%) adverse events also included constipation, dry mouth (xerostomia), 
heartburn/dydpepsia, taste alteration (dysgeusia), increase in ALT and AST, 
changes in creatinine, hypophosphatemia, muscle weakness, dizziness and cough. 
Less likely adverse effects (< 20%) are leukopenia, neutropenia, , abdominal pain, 
and mucositis/stomatitis. Also reported on vorinostat trials, but with the relationship 
to vorinostat still undetermined: allergy/immunology (vasculitis), cardiovascular 
(palpitations, tachycardia, hypertension, hypotension), coagulation (INR, PTT 
alterations), constitutional symptoms (fever, insomnia, rigors/chills, weight loss), 
death, dermatology/skin (alopecia, ecchymosis, pruritus, rash), gastrointestinal 
(colonic obstruction, dysphagia, esophagitis, flatulence, gastritis, heartburn,  
hemorrhage/bleeding 
(epistaxis, 
hemoptysis, 
melena, 
petechiae, 
subdural 
hematoma), infection (febrile neutropenia, infection), lymphatics (limb edema, 
swelling face), metabolic/laboratory (alkaline phosphatase, hyperbilirubinemia, 
hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, 
hypoalbuminemia, hypomagnesemia, hyponatremia, low serum bicarbonate), 
musculoskeletal/soft tissue (gait/walking, rib fracture), neurology (ataxia, confusion, 
depression, 
dizziness, 
sensory 
neuropathy, 
speech 
impairment, 
tremor), 
ocular/visual (eyelid ptosis), pain (back pain, chest pain, face pain, flank pain, 
gingival pain, groin pain, headache, joint pain, limb pain, muscle pain, neck pain, 
pharyngolaryngeal pain), pulmonary/upper respiratory (dyspnea, hiccoughs, pleural 
effusion, 
pneumonitis/pulmonary 
infiltrates, 
sinus 
congestion, 
wheezing), 
renal/genitourinary (urinary frequency, urinary incontinence, urinary retention), 
vascular (deep vein thrombosis). 
Dose limiting toxicities are anorexia, dehydration, diarrhea, and fatigue. Prothrombin 
time and INR prolongations have been reported in patients taking vorinostat 
concomitantly with coumarin derivative anticoagulants. Thus, monitor these patients 
more frequently for alterations in their coagulation parameters may be necessary.  
To prevent dehydration, patients should consume at least 2 liters of fluid orally, daily. 
If patients are experiencing dysgeusia, popsicles or Gatorade may be 
recommended. If diarrhea occurs, it should be managed with loperamide according 
to institutional guidelines. Nausea should be managed according to standard 
practice; 5HT-3 antagonists have proven effective. 
 
Vorinostat was evaluated in a panel of genetic toxicity assays; in vivo and in vitro 
assays were found to be positive. Therefore, vorinostat should not be taken by 
pregnant women. Both women and men of reproductive potential participating in 
vorinostat studies must be completely informed of the unknown risks of pregnancy 
and agree not to become pregnant or father a child during the time they are 
participating in the study until at least 30 days after the final dose. Further, 
appropriate contraception must be used. 
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Vorinostat-related Clinical or Laboratory Adverse Experiences by Preferred Term as 
experienced by ≥ 10% of all Patients  
 
Total Patients  (N=305) 
Related Experiences Only 
All Grades 
Grade 3-5 
n % 
n % 
Fatigue  
Nausea  
Diarrhoea 
 Anorexia     
Vomiting     
Hyperglycaemia  
Blood Creatinine Increased    
Weight Decreased  
Thrombocytopenia     
Constipation  
Dysgeusia    
Haemoglobin Decreased  
Dehydration 
Hypocalcaemia  
Platelet Count Decreased    
Dyspnoea    
Anaemia  
Hyponatraemia  
Alopecia    
Dry Mouth  
Aspartate Aminotransferase Increased  
Alanine Aminotransferase Increased  
Hypokalaemia    
Blood Alkaline Phosphatase Increased     
 Hypoalbuminaemia    
White Blood Cell Count Decreased    
195 (63.9)  
170 (55.7)  
151 (49.5) 
 141 (46.2) 
 100 (32.8)  
79 (25.9)  
75 (24.6)  
75 (24.6)  
69 (22.6)  
54 (17.7)  
54 (17.7)  
53 (17.4)  
45 (14.8)  
42 (13.8)  
41 (13.4)  
40 (13.1)  
36 (11.8)  
36 (11.8)  
35 (11.5)  
35 (11.5) 
 34 (11.1)  
33 (10.8)  
33 (10.8)  
31 (10.2)  
31 (10.2)  
31 (10.2)  
42 (13.8) 
 17 (5.6) 
 14 (4.6)  
15 (4.9)  
5 (1.6)  
10 (3.3)  
2 (0.7)  
4 (1.3)  
34 (11.1)  
3 (1.0)  
0 (0.0) 
 10 (3.3)  
25 (8.2)  
3 (1.0)  
13 (4.3) 
 1 (0.3)  
7 (2.3)  
5 (1.6) 
 0 (0.0)  
0 (0.0)  
2 (0.7) 
 1 (0.3) 
 6 (2.0)  
1 (0.3)  
1 (0.3) 
 4 (1.3)  
A patient is counted only once within a specific preferred term, even if more than one adverse experience with 
specific preferred term occurred. Adverse experience terms are from MedDRA Version 8.1  
 
 
3.3   Temozolomide 
   
3.3.1 Therapeutic Classification  
 
Alkylator agent, antineoplastic. 
 
3.3.2 Pharmacologic  Data   
 
Temozolomide (TMZ, Temodar®) is an orally administered alkylating agent with 
activity against malignant gliomas. It is a prodrug that spontaneously converts at 
physiologic pH to the active alkylating agent 5-(3- methyltriazen-1-yl)imidazole-4-
carboximide (MTIC) under physiologic conditions. The cytotoxicity of temozolomide 
is principally mediated through methylation of DNA at the O6 position of guanine 
Temozolomide is rapidly and completely absorbed after oral administration; peak 
plasma concentrations occur in 1 hour. Food reduces the rate and extent of 
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temozolomide absorption. Mean peak plasma concentration and AUC decreased by 
32% and 9%, respectively, and Tmax increased 2-fold (from 1.1 to 2.25 hours) when 
temozolomide was administered after a modified high-fat breakfast.  
 
Temozolomide is rapidly eliminated with a mean elimination half-life of 1.8 hrs and 
exhibits linear kinetics over the therapeutic dose range. Temozolomide has a mean 
apparent volume of distribution of 0.4 L/kg (%CV=13%). It is weakly bound to 
plasma proteins; the mean percent bound of drug-related total radioactivity is 15%.  
 
Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species 
MTIC and to temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-
imidazole-4-carboxamide (AIC), which is known to be an intermediate in purine and 
nucleic acid biosynthesis and to methylhydrazine, which is believed to be the active 
alkylating species. Cytochrome P450 enzymes play only a minor role in the 
metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the 
exposure to MTIC and AIC is 2.4% and 23%, respectively. Approximately 38% of 
the. administered temozolomide total radioactive dose is recovered over 7 days: 
37% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine 
is as unchanged temozolomide (5.6%) AIC (12%), temozolomide acid metabolite 
(2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of 
temozolomide is ~5.5 L/hr/m.  
 
3.3.3 Pharmaceutical Data  
 
Temozolomide is not directly active but undergoes rapid non-enzymatic conversion 
at physiologic pH to the reactive compound MTIC. The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs 
mainly at the O6 and N7 positions at guanine. Temozolomide should be stored at 
room temperature. The capsules are packaged in 30 cc 28 mm-48-Type I amber 
glass bottles (30 capsules/bottle) and should be stored between 2 and 30 degrees 
Centigrade. Capsules are stable for at least 30 months when stored in amber glass 
bottles at this temperature. 
 
3.3.4 Usual Dosage Range  
 
The typical dose regimen for patients with recurrent malignant glioma is 150 -200 
mg/m2/day orally days 1-5 every 28 days [12]. According to clinical circumstances 
the initial dosage may require reduction by 20 to 25% in patients with risk factors 
such as prior myelosuppressive therapy and poor performance status. Determining 
haematologic nadir by frequent  blood counts during initial courses is recommended 
for future dosage adjustment and scheduling of temozolomide.  
 
3.3.5 Route of Administration  
 
Oral.  
 
3.3.6 Formulation  
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Temozolomide (Temodar®) is supplied in white, opaque, preservative free, 2-piece, 
hard gelatin capsules in the following p.o. dosage strengths: 5 mg, 20 mg, 100 mg, 
140 mg, 180 mg and 250 mg. Capsules should not be opened or chewed. If 
capsules are accidentally opened or damaged, inhalation or contact with the skin 
should be avoided. Each capsule contains drug substance in combination with 
lactose, anhydrous NF, colloidal silicon dioxide NF, sodium starch glycolate NF, 
tartaric acid NF, and stearic acid NF. The capsule shells contain gelatin NF, titanium 
dioxide USP, and sodium lautyl sulfate NF.  
 
3.3.7 Supply: Provided by Merck, Sharp and Dohme. 
 
3.3.8 Side Effects and Toxicities  
 
3.3.8.1 Known Potential Adverse Events  
Hematologic: Thrombocytopenia, leukopenia, myelodysplastic syndrome 
Gastrointestinal: Nausea, vomiting, anorexia 
Hepatic: Elevated liver enzymes (reversible) 
Skin: Rash 
Neurologic: Convulsions, weakness (one side of the body), incoordination, paralysis 
Other: Constipation, diarrhea, stomatitis, fatigue, decreased performance status, 
headache 
 
A. Likely (occurring in more than 20% of patients) 
• fatigue  
• headache 
• seizures 
• alopecia 
• nausea 
• vomiting 
• constipation 
• anorexia 
• Lymphopenia 
 
B. Common (occurring in 3-20% of patients) 
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• dizziness 
• abnormal 
muscle 
movements/ 
coordination 
• abnormal gait 
• hemiplegia or partial 
paralysis 
• upper 
and/or 
lower 
extremity edema 
• weakness 
(such 
as 
weakness on one side 
of the body) 
• tickling/tingling 
sensation 
• pain (such as in the 
abdomen, joints, back, 
and/or muscles) 
• breast pain in females 
• memory problems 
• depression  
• difficulty sleeping 
• drowsiness 
• skin rash 
• pruritus 
• dry skin 
• mucositis  
• dysphagia 
• dysgeusia 
or 
taste 
changes 
• diarrhea  
• excess steroid in the 
body 
(possible 
bruising 
and/or 
increase in size of the 
face and/or neck) 
• viral infection 
• anxiety 
• leukopenia 
• weight gain 
• loss 
of 
urinary 
control  
• urinary 
tract 
infection  
• frequent urination 
• abnormal vision 
• blurry vision  
• diplopia or double 
vision 
• fever 
• cough 
• sore throat 
• sinusitis  
• dyspnea 
• allergic reaction  
• confusion 
• neutropenia 
thrombocytopenia 
 
 
C. Rare but serious (occurring in fewer than 3% of patients) 
 
• bone 
marrow 
disease 
where not enough blood 
cells are made 
•  hallucinations 
•  nervous system disease 
(possible 
pain 
and/or 
weakness) 
•  neuropathies 
(nerve 
damage- 
possible 
numbness, tingling, and 
pain) 
• hyperglycemia 
(possible 
diabetes) 
• hypokalemia 
(possible 
weakness) 
• severe allergic reaction 
 
• new 
occurrence 
of 
cancer 
(including 
myeloid leukemia) 
• allergic skin reaction 
• severe skin damage 
with loss of a large 
portion of skin  
•  weight loss 
•  fever due to low white 
blood         
     cell counts 
•  bruising 
•  hemorrhage 
•  Steven-Johnson 
Syndrome 
• damage 
from 
radiation (such as 
skin damage) 
• pneumonitis (lung 
inflammation) 
• flu-like symptoms 
• injection 
site 
reactions 
(skin 
redness, irritation, 
pain, 
itching, 
swelling, 
and/or 
warmth) 
• opportunistic 
infection 
• herpes 
infection 
causing 
painful 
skin rash (shingles) 
 
 
3.3.9 
Special Populations: 
3.3.9.1  Creatinine Clearance: Population pharmacokinetic analysis indicates that 
creatinine clearance over the range of 36-130 mL/min/m2 has no effect on the 
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clearance of temozolomide after oral administration.  The pharmacokinetics of 
temozolomide have not been studied in patients with severely impaired renal 
function (CLcr < 36 mL/min/m2). Caution should be exercised when temozolomide is 
administered to patients with severe renal impairment.  Temozolomide has not been 
studied in patients on dialysis. 
3.3.9.2  Hepatically Impaired Patients:  In a pharmacokinetic study, the 
pharmacokinetics of temozolomide in patients with mild to moderate hepatic 
impairment (Child’s-Pugh Class I-II) were similar to those observed in patients with 
normal hepatic function.  Caution should be exercised when temozolomide is 
administered to patients with severe hepatic impairment.   
3.3.9.3   Gender: Population pharmacokinetic analysis indicates that women have an 
approximately 5% lower clearance (adjusted for body surface area) for 
temozolomide than men. Women have higher incidences of grade 4 neutropenia and 
thrombocytopenia in the first cycle of therapy than men. 
3.3.9.4   Age: Population pharmacokinetic analysis indicates that age (range 19-78 
years) has no influence on the pharmacokinetics of temozolomide. In the anaplastic 
astrocytoma study population, patients 70 years of age or older had a higher 
incidence of grade 4 neutropenia and grade 4 thrombocytopenia in the first cycle of 
therapy than patients <70 years of age.  In the entire safety database, however, 
there did not appear to be a higher incidence in patients ≥70 years of age. 
3.3.9.5   Drug-Drug Interactions:  
In a multiple dose study, administration of 
temozolomide with ranitidine did not change the Cmax or AUC values for 
temozolomide or MTIC. Population analysis failed to demonstrate any influence of 
co-administered dexamethasone, prochlorperazine, phenytoin, carbamazepine, 
ondansetron, H2-receptor antagonists, or phenobarbital on the clearance of orally 
administered temozolomide. 
 
The following side effects have been reported in research studies 
with 
temozolomide. 
However, 
their 
causality 
related 
to 
temozolomide is uncertain: 
 
• BUN blood level increase 
• creatinine blood elevated 
• lymphopenia 
• thrombocytopenia 
• neutropenia 
 
• death 
• hypoxia 
• weight loss 
• epistaxis 
• sepsis 
• cholecystitis 
• pancreatitis 
• GI perforation 
• dehydration 
 
3.3.9.6   Temozolomide is potentially mutagenic and should be handled with 
appropriate precautions by both staff and patients.  Capsules should not be opened.  
If capsules are accidentally opened or damaged, rigorous precautions should be 
taken with the capsule contents to avoid inhalation or contact with the skin or 
mucous membranes.  Procedures for proper handling and disposal of anticancer 
drugs should be considered. 
 
3.3.10 Contraindications: Temozolomide is contraindicated in patients who have 
a history of a hypersensitivity reaction to any of its components or to DTIC. 
 
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3.3.11 Pregnancy Category D  
Temozolomide may cause fetal harm when administered to a pregnant woman.  
There are no adequate and well-controlled studies in pregnant women.  If this drug 
is used during pregnancy, or if the patient becomes pregnant while taking this drug, 
the patient should be apprised of the potential hazard to the fetus.  Women of 
childbearing potential should be advised to avoid becoming pregnant during 
therapy with temozolomide.   
 
Treatment of a man with temozolomide may increase the risk of birth defects if he 
causes a woman to become pregnant while he is taking temozolomide.   Men 
treated with temozolomide may have difficulty causing a woman to become pregnant 
after their treatment is completed.  Men receiving temozolomide should be directed 
to use effective contraception while they are being treated.  There is insufficient data 
to know what the risk of subsequent problems with fertility will be.  Similarly, women 
who are treated with temozolomide may have difficulty becoming pregnant in the 
future and may at be at increased risk of having children with birth defects.   There is 
insufficient evidence to determine what the risk of these complications will be. 
  
 
 
4.0  
ELIGIBILITY CRITERIA 
 
4.1 
Patients with histologically proven supratentorial glioblastoma multiforme, 
gliosarcoma  or anaplastic glioma will be eligible for the Phase I component of 
this protocol. Anaplastic gliomas include anaplastic astrocytoma (AA), anaplastic 
oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant 
glioma NOS (not otherwise specified). Patients will be eligible if the original 
histology was low-grade glioma and a subsequent histological diagnosis of a 
malignant glioma is made. Only patients with histologically proven supratentorial 
glioblastoma multiforme or gliosarcoma will be eligible for the Phase II 
component.  
 
4.2 
Patients must have shown unequivocal evidence for tumor recurrence or 
progression by MRI scan and should have failed radiation therapy. The scan 
done prior to study entry documenting progression will be reviewed by the 
treating physician to document changes in tumor dimension to confirm 
recurrence. Patients with prior therapy that included interstitial brachytherapy or 
stereotactic radiosurgery must have confirmation of true progressive disease 
rather than radiation necrosis. 
 
4.3 
Patients may have had up to 2 prior relapses provided the functional status and 
other eligibility criteria for enrollment are met. 
 
4.4 
All patients must sign an informed consent indicating their awareness of the 
investigational nature of this study in keeping with the policies of this hospital. 
 
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4.5 
The baseline on-study MRI should be performed within 14 days (+ 3 working 
days) prior to registration and on a steroid dosage that has been stable or 
decreasing for at least 5 days.  If the steroid dose is increased between the date 
of imaging and the initiation of therapy (or at that time), a new baseline MRI is 
required.  The same type of scan, i.e., MRI, must be used throughout the period 
of protocol treatment for tumor measurement. 
 
4.6 
Patients having undergone recent resection of recurrent or progressive tumor will 
be eligible as long as all of the following conditions apply: 
 
a) They have recovered from the effects of surgery. 
 
b) Evaluable or measurable disease following resection of recurrent tumor is not 
mandated for eligibility into the study.  
 
c) To best assess the extent of residual measurable disease post-operatively, a 
MRI should be done no later than 96 hours in the immediate post-operative 
period or 4-6 weeks post-operatively. 
 
4.7 
Patients must be 18 years old or older. 
 
4.8 
Patients must have a Karnofsky performance status (KPS) equal or greater than 
60 (Appendix G). 
 
4.9 
Patients must have recovered from the toxic effects of prior therapy to < grade 2 
non hematological or grade 2 or lesser hematological toxicity per CTC ver 3 
(except deep vein thrombosis – see section 5.3): 4 weeks from prior cytotoxic 
therapy and/or at least two weeks from vincristine, 6 weeks from nitrosoureas, 3 
weeks from procarbazine administration, and 1 week for non-cytotoxic agents, 
e.g., interferon, tamoxifen, cis-retinoic acid, etc. (radiosensitizer does not count).  
Patients who receive anticancer agents for non-therapeutic purposes unrelated 
to this study (such as presurgically for obtaining pharmacology data for the 
agent) will be eligible to enter the study provided they have recovered from the 
toxic effects of the agent  if any. Because the trial is based on the hypothesis that 
the combination of agents used will be synergistic in their effects, and that HDAC 
inhibition will potentially overcome resistance to retinoids, prior treatment with 
cRA is allowed. Any questions related to the definition of non-cytotoxic agents 
should be directed to the Study Chair. 
 
4.10 Patients must have adequate bone marrow function (ANC> 1,500/mm3 and 
platelet count of > 100,000/mm3), adequate liver function (SGPT < 3 times 
normal and alkaline phosphatase < 2 times normal, bilirubin <1.5 mg/dl), 
adequate renal function (BUN and creatinine <1.5 times institutional normal) and 
normal serum amylase and lipase prior to starting therapy. Elevated cholesterol 
and triglycerides are not a contraindication to study enrollment, but should be 
managed as clinically appropriate by the treating physician. 
 
4.11 Patients with a history of any other cancer (except non-melanoma skin cancer or 
carcinoma in-situ of the cervix or bladder), unless in complete remission and off 
of all therapy for that disease for a minimum of 3 years are ineligible. 
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4.12 Patients must not have:  
a) active infection 
b) disease that will obscure toxicity or dangerously alter drug metabolism, 
especially liver disease including cirrhosis or hepatic dysfunction 
c) serious intercurrent medical illness 
d) prior recurrence with other HDAC inhibitors. However, patients who have 
received anticancer agents for non-therapeutic purposes (for eg., as part of a 
pharmacology study without therapeutic intent) will remain eligible for enrollment 
into the study 
 
4.13 Patients receiving valproic acid (VPA), an anticonvulsant drug with HDAC 
inhibitor properties, will be excluded, unless they are switched to an alternative 
agent prior to treatment initiation. No wash out period is required. 
 
4.14  Prior treatment with dose dense regimens of temozolomide  is not allowed (e.g, 7 
days on/7 days off, 21 day/28 day and daily low dose continuous dosing). 
However, standard day 1-5 dosing and low dose daily dosing as part of 
chemoradiation therapy are allowed . 
 
4.15 Patients receiving treatment with other antiepileptic medications will not be 
excluded. Vorinostat is not metabolized by cytochrome P450 3A4 (CYP 3A4). 
However, vorinostat may potentially suppress CYP 3A4 activity. Therefore, 
patients should preferably be treated with non-enzyme inducing anti-epileptic 
medications to avoid any potential interactions with vorinostat. However, the use 
of non-enzyme inducing anti-epileptic medications is not mandatory. If enzyme-
inducing antiepileptic drugs are used, monitoring of drug levels should be 
considered, as considered clinically appropriate by the treating physician. 
 
4.16 Patients with a known allergy to any component of vorinostat, or a known allergy 
to temozolomide and/or isotretinoin will be excluded. 
 
 
4.17 Patients must be willing and able to comply with the FDA mandated iPLEDGE 
program for treatment with isotretinoin (cRA). Patients must sign specific 
informed consents for treatment with cRA, as mandated by iPLEDGE guidelines. 
Women of childbearing potential must not be pregnant, must not be breast-
feeding and must practice adequate contraception (please refer to 6.4 and 
Appendix I for details and definitions – woman of childbearing potential; adequate 
methods of contraception).  
 
4.18  Male patients on treatment with vorinostat must agree to use an adequate 
method of contraception for the duration of the study, and for 30 days after the 
last dose of study medication (please refer to Appendix I for definition of 
adequate methods of contraception). 
 
4.19  Patient must be able to tolerate the procedures required in this study including 
periodic blood sampling, study related assessments, and management at the 
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treating institution for the duration of the study. Inability to comply with protocol or 
study procedures (for example, an inability to swallow tablets) will be an 
exclusion criteria. 
 
4.20 This study was designed to include women and minorities, but was not designed 
to measure differences of intervention effects. Males and females will be 
recruited with no preference to gender. 
 
4.21 No exclusion to this study will be based on race. The malignant glioma patient 
population treated at MDACC over the past year is as follows: 
 
 
American Indian or Alaskan Native - 0 
 
Asian or Pacific Islander - <2% 
 
Black, not of Hispanic Origin - 3% 
 
Hispanic - 6% 
 
White, not of Hispanic Origin - 88% 
 
Other or Unknown - 2% 
 
Total-100% 
 
 
5.0 TREATMENT PLAN 
 
5.1. Phase I Component 
 
The Phase I component of the trial was designed with three treatment arms (see 
below). This component is a non randomized trial in which Arm 1 and Arm 2 were to 
be opened simultaneously with consecutive patients enrolled alternately to each 
arm, and sequentialy to each dose level. If the MTD was reached earlier in one arm, 
all subsequent patients were to be enrolled to the other arm. Once the MTD for Arm 
1 and Arm 2 was known, Arm 3 would begin accrual. A maximum of 54 patients 
were to be enrolled in this component of the trial. The MTDs obtained in the Phase I 
component were planned to be used as the Phase II dose in the next component of 
the trial. 
 
5.1.1. Arm 1 – Vorinostat plus isotretinoin 
 
This arm assessed the MTD of vorinostat in combination with a fixed dosage of 
isotretinoin (cRA) as shown in the table below.  A cycle of treatment was 28 days (+ 
3 days); the treatment schedule began with cRA on days 1-21. The total daily dose 
was to be given orally, divided BID (twice a day). Vorinostat was  administered on 
days 1-14.  The total daily dose was given once daily orally. Days 22-28 was 
considered as a no-treatment "rest" period.  
 
A conventional phase I design was used with 3 patients enrolled into the first dose 
level and monitored for 3 weeks. If no DLT was seen, the next 3 patients were to be 
enrolled at the next dosage level. A maximum of three dosage levels will be utilized 
as shown in the table below. If no DLT was noted after dose escalation to Level III, 
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these doses were to be utilized for the phase II components of the study.  If 1/3 
patients shows ≥ grade 3 toxicity, the cohort was to be expanded to 3 more patients, 
If 2/6 patients experience ≥ grade 3 toxicity, the DLT was considered reached, and 
previous (lower) dosage level was to be declared as the MTD of vorinostat in 
combination with cRA.  
 
Level 
Arm 1 
 
Vorinostat 
(mg/day x 14 days) 
cRA 
(mg/m2/day x 21 days) 
0 (starting dose) 
300 mg  
100 
I 
400 mg  
100 
II 
500 mg  
100 
 
This arm of the trial completed accrual as planned and an MTD was established for 
the combination of vorinostat (400 mg/day on days 1-14) and isotretinoin (100 
mg/m2/day on days 1-21) on a 28 day schedule.  We propose to use this dose in the 
phase II trial. 
 
 
5.1.2. Arm 2 – Temozolomide plus isotretinoin 
 
This arm was originally designed to assess the MTD of carboplatin (CBT) in 
combination with fixed doses of isotretinoin (cRA). The accrual to this arm of the trial 
was also completed and the MTD for this combination was established with 
carboplatin (AUC 5 on day 1) and isotretinoin (100 mg/m2/day on days 1-21). 
However, in the current proposal, we will not use carboplatin and will replace this 
with temozolomide.  Thus, the combination of interest in Arm 2 will be dose-dense 
temozolomide with isotretinoin. A recent phase I trial of temozolomide in combination 
with several different agents has established the MTD of temozolomide adminstered 
in combination with isotretinoin at 150 mg/m2/day of temozolomide on days 1-7 and 
days 15-21 in patients with glioblastoma (Gilbert et al, Neuro-oncology 2010).  Thus, 
we propose to use this regimen in the phase II portion of the current trial without the 
need for a phase I component.   
 
5.1.3. Arm 3 – Vorinostat plus isotretinoin plus temozolomide 
 
This arm will assess the MTD of vorinostat and temozolomide in combination with 
fixed doses of cRA. The enrollment will proceed as outlined for Arm 1 and 2 (cohorts 
of 3 patients enrolled to each dose level), declaring MTD for vorinostat in 
combination with temozolomide and cRA once DLT is noted. In this arm, cRA will be 
given on days 1-21 and vorinostat on days 1-7 and 15-21 . Temozolomide will be 
administered orally on days 1-7 and 15-21. Days 22-28 will be considered a no-
treatment "rest" period. A maximum of three dose levels of vorinostat  will be used 
as shown in the table below. 
 
Level 
Arm 3 
 
Vorinostat 
(mg/day x days 1-7 & 
15-21) 
cRA 
(mg/m2/day 
x 
21 
days) 
Temozolomide 
(mg/m2/day 
on 
days 1-7 & 15-21 
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-III 
300 
100 
100 
-II 
300 
100 
125 
-I 
400 
100 
125 
0 (starting dose) 400 
100 
150  
I 
500 
100 
150 
 
5.1.3.1 Escalation of Dose Level 
• If the initial cohort of patients at starting dose level 0 do not experience DLT, 
the next cohort of patients will be treated by dose escalation to  level I (with 
increase in the dose of vorinostat). If no patients experience DLT in this 
cohort, 3 more patients will be enrolled to expand this cohort to a total of 6 
patient to confirm that MTD has been achieved. If no DLT is noted or if only 
1/6 patients experience DLT after this expansion of level I, this dose level will 
be declared the MTD and hence the phase II dose.  
• If 2/6 patients have DLT after expansion of dose level I, dose level 0 will be 
declared as the MTD and hence the phase II dose. 
 
5.1.3.2 De-escalation of Dose Level 
• If Dose level 0 exceeds the MTD, lower doses will be studied as noted in the 
table above. If 1/3 patients have DLT at any dose level, the cohort will be 
expanded by 3 more patients. If ≥2/6 patients experience DLT, the MTD will 
be considered as being exceeded and the dose will be de-escalated to the 
next lower dose level and 3 new patients will be enrolled at that level. If none 
or only 1/6 patients experience DLT after dose de-escalation to the lower 
level, this dose level will be declared as the MTD, and will be utilized for the 
phase II component of the study.  
 
 
5.2. Phase II Component 
 
5.2.1. Non-surgical Arm  
 
In this component, patients will be randomized between three competing treatment 
arms: vorinostat + cRA, versus TMZ + cRA, versus vorinostat + cRA + TMZ using an 
adaptive randomization design (see 11.0 Statistical Section). The dosage of agents 
in each arm will be derived from the MTD of the combination determined in the 
phase I component of the study. The treatment schedule will be identical to that 
described above in the phase I component, with each course comprising 28 days (+ 
3 days). Patients will continue treatment for at least one year from registration 
provided they experience neither tumor progression nor unacceptable toxicity (see 
8.9). Treatment beyond this period is at the discretion of the treating physician after 
discussion with the patient. Vorinostat will continue to be provided free of charge to 
patients continuing treatment beyond 1 year. 
 
Optional procedures: if available, brain tumor tissue from prior surgical procedures 
(original surgery, or definitive surgery, or the surgery closest to initiation of this 
clinical trial) will be obtained for determination of acetylation status and p21 levels 
(see 6.7). Blood samples for acetylation status of histones and p21 levels in 
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peripheral mononuclear cells will be also collected at baseline prior to treatment 
(6.6). Patients enrolled in arms 1 (vorinostat + cRA) and 3 (vorinostat + cRA + TMZ) 
will be evaluated with blood samples before and after treatment with vorinostat in 
day 1 of cycles 1 and 2 (see 7.10). 
 
5.2.2. Surgical Arm  
 
Ten patients who require resection for recurrent glioblastoma multiforme will be 
included in this arm of the study. These patients will receive treatment with 
vorinostat at a dose of 400 mg once daily for 3 consecutive days prior to surgery. 
Blood samples for acetylation status of histones and p21 levels in peripheral 
mononuclear cells will be collected at baseline prior to treatment, and after the first 
dose of vorinostat. The last dose prior to surgery will be administered the morning of 
surgery within 6 hours of the tumor removal. Tumor tissue and intraoperative blood 
samples will be obtained for analysis of drug levels, histone acetylation and p21 
levels. Approximately 2 weeks after surgery is performed, each patient will be 
randomized to one of the three treatment arms of the phase II component (arm 1: 
vorinostat + cRA; arm 2: TMZ + cRA; arm 3: vorinostat + cRA + TMZ). Patients 
enrolled in arms 1 and 3 will be evaluated with blood samples before and after 
treatment with vorinostat in cycles 1 and 2 as described for patients in the non-
surgical arm (see 5.2.1, and 7.10). In surgical patients, cycle 1 will be the first cycle 
of treatment after surgery. 
 
Progression Free Survival (PFS)  in patients enrolled in the surgical arm will be 
determined from the date of randomization into the chemotherapy arms (i.e. after 
surgery for resection of recurrent tumor), and not from the date of registration in the 
trial. 
 
5.3. Definition of dose limiting toxicities (DLT) 
 
Toxicities will be graded according to the Common Terminology Criteria for Adverse 
events (CTCAE) Version 3.0.  (see Appendix B). If multiple toxicities are seen, the 
presence of DLT should be based on the most severe toxicity experienced. DLT will 
be defined as any of the following events occurring during treatment  and attributable 
to the study drugs: 
 
5.3.1  Any grade 4 hematological toxicity excluding lymphopenia . (if the toxicity is 
Grade 4 neutropenia without fever, it must NOT resolve/regress to ≤ Grade 1 within 
7 days of onset to be considered a DLT). 
 
5.3.2  Any non-hematologic grade 3 toxicity, weight gain (in patients on steroids), 
alopecia, and venous thromboembolic disease *. Grade 3 nausea, vomiting, or 
diarrhea that cannot be controlled by medical therapy will be considered dose-
limiting. Isolated laboratory abnormalities not of clinical significance will be discussed 
with the IRB and the decision to declare these DLTs will be based on the IRB 
recommendations. 
 
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5.3.3  Failure to recover from toxicities to be eligible for re-treatment within 4 weeks 
of the last dose of the drugs.  
 
*Non-Relevant Toxicities for Brain Tumor Protocols 
 
Lymphopenia is a common finding among patients with primary brain tumors and is 
directly attributable to concurrent use of corticosteroids.  To date, even Grade III 
lymphopenia has not been associated with a worsening of clinical outcome.  
Therefore, we will not consider this parameter in the determination of optimal dosing 
of drugs. 
 
Weight gain is a common finding among patients with primary brain tumors.  This too 
is directly attributed to the concurrent use of corticosteroids.  Doses of steroids or 
study agents will not be modified as a consequence of weight gain.  Corticosteroid 
dosage will be based on maintenance of control of edema in the brain and the 
standard clinical practice to use the minimal effective dose of corticosteroids will be 
employed. 
 
Alopecia is a common occurrence in patients with brain tumors as a consequence of 
cranial radiotherapy.  Alopecia will not be recorded or graded as toxicity. 
 
Venous thromboembolic disease is a common complication occurring in up to 30% 
of patients with malignant gliomas [32, 33]. In this study, patients who develop deep 
vein thrombosis may receive anticoagulation and resume therapy  once they are 
stable on anticoagulation. Grade III deep vein thrombosis will not be considered a 
DLT. 
 
 
5.4. Dose modifications 
 
5.4.1  Subsequent Cycles 
 
Treatment cycles will be repeated every 28 days (+ 2 days) from day 1 provided that 
the tumor has not progressed and the patient has recovered from treatment-related 
adverse events associated with a prior course. Recovery has occurred once all of 
the following conditions have been met:   
 
a) ANC >1500/mL; 
b) Platelet Count >100,000/mL; 
c) All drug-associated non-hematological toxicities have recovered to either 
Grade 0 or 1(except for deep venous thrombosis as below). 
 
If recovery has not occurred by Day 28 (+ 3 days), the subsequent cycle will be 
delayed until these criteria have been met. If the patient has not recovered within 4 
weeks of rest, he/she will be taken off study. However, if the patient develops a 
lower extremity deep venous thrombosis and requires anticoagulation or intervention 
(grade 3 toxicity), treatment may be restarted after a 2 week rest period if the patient 
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is stably anticoagulated and is judged medically stable to begin chemotherapy, in the 
opinion of the treating physician. (Please note: DVT is graded in the CTC version 3.0 
as grade 1= not defined, grade 2= DVT without need for anticoagulation or 
intervention, grade 3= DVT needing anticoagulation or intervention). 
 
The administration of vorinostat, isotretinoin and temozolomide in subsequent cycles 
will continue at the same doses without interruption as long as there is no tumor 
recurrence or progression and toxicity is acceptable.  
 
5.4.2  Dosage Reduction  
 
Patients experiencing toxicity will be dose reduced according to the agent causing 
the toxicity. Because of the different profile of side effects of agents combined in 
Arms 1 and 2 (vorinostat + cRA; TMZ + cRA), no significant overlapping toxicities 
are expected. In case of thrombocytopenia or anemia in Arm 3 (vorinostat + cRA + 
TMZ), temozolomide will be dose-reduced first, and then vorinostat on an alternating 
basis for each time a dose reduction becomes necessary. 
 
5.4.2.1  Vorinostat 
 
 
 
Vorinostat will be administered from day 1 -14 in arm 1 and on days 1-7 and 15-
21 in arm 3. Treatment will be initiated at the MTD dose determined in the phase 
I component of the trial for each arm. This dose will be maintained as long as 
there are no toxicities > grade 3. For grade 3 or greater toxicities, treatment will 
be withheld and the patients will be monitored until toxicities resolve to < grade 2 
(except for deep venous thrombosis as noted in section 5.3). Subsequent 
treatment will be at one dose level lower than the one that caused the toxicity. If 
there is grade 3 or greater non-hematologic toxicity, a minimum of 2-week rest 
period will be required. Subsequently, patients will restart treatment at one dose 
level less than the one that resulted in the toxicity as indicated below.  
 
Dose adjustments for the subsequent cycles: dose will be one level below 
the dose that produced toxicity of grade 3 or greater per dose schedule changes 
indicated below. If grade 3 or 4 toxicity recurs, patients will again discontinue the 
vorinostat until toxicity returns to grade 1 or less. The estimated dose levels 
below are shown for various MTD that may be determined in the phase I study. 
 
In case of thrombocytopenia or anemia in Arm 3 (vorinostat + cRA + TMZ), TMZ 
will be dose-reduced first, and then vorinostat on an alternating basis for each 
time a dose reduction becomes necessary. 
 
 
Dose Level:             -2                                   -1                                        0                     
Drug  
 
 
 
 
 
                 MTD Phase I 
___________________________________________________________________  
Vorinostat 
N/A 
 
 
200 mg once daily 
   300 mg once daily 
 
 
 
 
200 mg once daily        300 mg once daily 
   400 mg once daily  
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300 mg once daily        400 mg once daily           500 mg once daily 
 
 
 
 
 
Only 2 dose reductions of vorinostat are permitted as above. If the patient 
experiences grade 3 or greater toxicity after 2 dose reductions, he/she will be 
taken off study. If starting dose is 300 mg once daily, only 1 dose reduction of 
vorinostat is allowed. 
 
5.4.2.2 Isotretinoin 
 
Isotretinoin will be administered from day 1 to day 21 in the 3 arms of the study 
at an initial dose of 100 mg/m2/day. Doses will be rounded down, depending on 
body surface area and available capsule sizes. Treatment will continue at the 
same dose as long as there are no toxicities > grade 3. For grade 3 or greater 
toxicities, treatment will be withheld and the patients will be monitored until 
toxicities resolve to < grade 2 (except for deep venous thrombosis as noted in 
Section 5.3).  
 
Dose adjustments for the subsequent cycles: Subsequent cycles will start 
(as long as the treatment is beneficial) after resolution of toxicities to grade 1 or 
less (except for deep venous thrombosis as noted in Section 5.3).  A minimum 
of 2-week rest period will be required if there is grade 3 or greater non-
hematologic toxicity.   
 
Dosage of cRA for the subsequent cycle will be one dose level below the dose 
that produced toxicity of grade 3 or greater as shown below. 
 
Dose level:                    -2                            -1                           0____ 
Isotretinoin 
       50 mg/m2            75 mg/m2 
        100mg/m2 
 
Only 2 dose reductions of cRA are permitted. If the patient experiences grade 3 
or greater toxicity after two dose reductions, he/she will be taken off study. 
 
5.4.2.3 Temozolomide 
 
Dosing is based on adverse events (AEs) during the prior treatment cycle. If 
multiple AEs are seen, the dose administered should be based on the dose 
reduction required for the most severe grade of any single AE.  
 
Dose Level 
Dose mg/m2 
Remarks 
- 2  
75 
Reduction if prior AE 
-1  
100 
Reduction if prior AE 
 0 
125 
Starting dose for cycle 1; increase to 
150 mg/m2 for cycle 2 and beyond if 
non hematologic toxicity ≤ grade 2 
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and hematologic toxicity ≤ grade 1 
+1 
150 
Highest possible dose level  
 
a) First Cycle: Temozolomide will be initiated at a dose of 125 mg/m2/day.  
 
b) Second Cycle: The dose of temozolomide will be determined according 
to: (1) treatment related non-hematologic AE during the preceding 
treatment cycle, as well as (2) the worst ANC and platelet counts. For 
patients at dose level 0, the dose may be increased to 150 mg/m2/dose 
for cycle 2 and beyond. If this dose is not tolerated, the dose may be 
reduced to the previous dose level. 
c) Delay: On day 1 of each cycle (within the prior 72 hours), ANC ≥ 1.5 x 
109/L, platelet count ≥ 100 x 109/L and all grade 2, 3 or 4 non-
hematologic AEs (except for alopecia, nausea, vomiting, weight change 
or DVT/PE – see section 5.3.3 – nonrelevant toxicities) must have 
resolved (to grade ≤ 1). For DVT/PE, the patient must have had adequate 
management of the event and be medically stable as determined by the 
treating physician prior to resuming treatment – this will be considered on 
a case by case basis after discussion between the treating physician and 
the study chair. 
 
 
If AEs persists, treatment should be delayed by 1 week for up to 4 
consecutive weeks. If, after 4 weeks of delay, all treatment related AEs 
have still not resolved (to grade ≤ 1): then any further treatment with 
temozolomide should be stopped.  
 
Dose Escalations and Reductions: If, during the first cycle, all 
hematologic AEs observed were ≤ grade 1 and treatment related non-
hematologic AEs observed were grade ≤ 2 (except alopecia, lymphopenia, 
nausea, vomiting, weight gain and DVT/PE) then the temozolomide dose 
can be raised to 150 mg/m2/dose for subsequent cycles.  
 
Dose reductions: If any treatment related non-hematologic AE observed 
was grade > 2 (except alopecia, lymphopenia, nausea, vomiting, weight 
gain and DVT/PE) and/or if platelets < 50 x 109/L and/or ANC < 1 x 109/L, 
then the dose should be reduced by one dose level. Patients who require 
more than three dose reductions will have treatment stopped. 
 
If any treatment-related non-hematologic AE observed was grade 4 (except 
alopecia, lymphopenia, nausea, vomiting, weight gain and DVT/PE)  then 
temozolomide treatment should be stopped.  
 
Subsequent cycles: Any dose reductions of temozolomide will be 
determined according to: (1) non-hematologic AE during the preceding 
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treatment cycle, as well as (2) the lowest ANC and platelets observed. No 
dose escalation should be attempted. The same dose reductions as for the 
second cycle should be applied. Important: If the dose was reduced or 
delayed for AEs, there will be no dose re-escalation in subsequent 
treatment cycles.  
 
Summary of Dose Modifications or Discontinuation for Temozolomide-Related 
Adverse Events 
 
Worst Treatment-Related Non-Hematologic AE (except for alopecia, nausea, and 
vomiting) During the Previous Cycles 
Grade 
Dose Modification 
0-2 
No dose modifications for non-hematologic AEs. Dose reductions based on ANC 
and platelet counts are applicable.  
3 
Reduce by one dose level (except alopecia, lymphopenia, nausea, vomiting, 
weight gain and DVT/PE).  
4 
Stop (except alopecia, lymphopenia, nausea, vomiting, weight gain and DVT/PE). 
Dose modifications based on ANC and platelet counts are not applicable.  
 
Worst Treatment-Related Hematologic AE During the Previous Cycle 
 
Worst AE 
Platelets 
 
≥100 x 109/L  
50 – 99 x 109/L  
< 50 x 109/L  
 
≥ 1.5 x 109/L  
Dose unchanged  
Dose unchanged  
Reduce by 1 dose 
level  
ANC  
≥1 & <1.5 x 109/L  
Dose unchanged  
Dose unchanged  
Reduce by 1 dose 
level  
 
< 1 x 109/L  
Reduce by 1 dose level  Reduce by 1 dose level  
Reduce by 1 dose 
level  
 
Note: A complete blood count must be performed on days 14 and 28 (± 72 
hours) after the first daily dose of each treatment cycle.  
Hematologic AE on Day 1 of Each Cycle (within the prior 72 hours before Day 
1) 
AE 
Delay 
ANC< 1.5 x 109/L and/or 
Platelet count < 100 x 
109/L 
Delay up to 4 weeks until all resolved. If unresolved 
after 
4 
weeks 
then 
stop. 
If 
resolved, 
dose 
delay/reductions based on non-hematologic AEs are 
applicable. If treatment has to be delayed for AEs, 
then no escalation is possible.  
 
Non-Hematologic AE (except alopecia, lymphopenia, nausea, vomiting, weight 
gain and DVT/PE)  
On Day 1 of Each Cycle (within the prior 72 hours) 
Grade 
Delay 
2-4 
Delay up to 4 weeks until all resolved (to grade ≤ 1). If unresolved after 4 
weeks, then stop. If resolved, dose delay/reductions based on ANC and 
platelets are applicable. If treatment has to be delayed for AE, then no 
escalation is possible.  
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In case of thrombocytopenia or anemia in Arm 3 (vorinostat + cRA + TMZ), TMZ 
will be dose-reduced first, and then vorinostat on an alternating basis for each 
time a dose reduction becomes necessary. 
 
A minimum of 4 weeks of treatment shall be required for a patient to be 
considered as having received an adequate trial to evaluate efficacy. All patients 
will be considered evaluable for toxicity and will be followed for at least 30 days 
after completion of treatment.    
 
5.5 Supportive care 
 
1. G-CSF and erythropoetin administration: routine prophylactic use is not 
permitted. However, therapeutic use in patients with complications (severe 
neutropenia with fever or anemia), may be considered. 
 
2. Steroids: should be used in the smallest dose to control symptoms of cerebral 
edema, and discontinued if possible. 
 
3. Antiepileptic medications: should be used as indicated. Treatment with valproic 
acid is not allowed. Patients should preferably be treated with non-enzyme 
inducing antiepileptic medications to avoid any potential interactions with 
vorinostat. For patients on treatment with enzyme-inducing antiepileptic drugs, 
clinically relevant monitoring of drug levels is recommended, as considered 
appropriate by the treating physician. 
 
4. Antiemetics: prophylactic and therapeutic use is allowed. 
 
5. Other concomitant medications: therapies considered necessary for the well-
being of the patient may be given at the discretion of the treating physician 
including prophylaxis for pneumocystis carinii pneumonia (PCP). All concomitant 
medications should be recorded. 
 
 
6.0  
PRE-STUDY EVALUATION 
 
6.1   A complete history and neurological examination (including height, weight and 
Karnofsky Performance Status), as well as documentation of evaluable disease 
shall be performed on all patients within 14 days (+ 3 working days) of study 
entry.  
 
6.2 
The treating physician will review a Gd-DPTA MRI scan done prior to study entry 
documenting progression. For non-surgical arm patients, a baseline scan should 
be performed within 14 days (+ 3 working days) of registration, with day 
0=registration date. The baseline on-study MRI should be performed on a steroid 
dosage that has been stable or decreasing for at least 5 days. If the steroid dose 
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is increased between the date of imaging and the initiation of therapy (or at that 
time), a new baseline MRI is required.  
 
6.3 
Pre-treatment laboratory tests will include CBC, differential, platelets, PT, PTT, 
INR, total protein, albumin, calcium, phosphorus, magnesium, glucose, BUN, 
creatinine, sodium, potassium, uric acid, total bilirubin, alkaline phosphatase, 
LDH, SGPT (ALT), SGOT (AST), amylase, lipase, lipid panel (total cholesterol, 
HDL-cholesterol, LDL-cholesterol, triglycerides), and a pregnancy test for women 
of child bearing potential (see 6.4 and Appendices I and J). Anticonvulsant levels 
in patients on treatment with enzyme-inducing antiepileptic drugs (phenytoin, 
phenobarbital, carbamazepine) will also be obtained if considered appropriate by 
the treating physician. Blood tests must be performed within 14 days (+ 3 working 
days) of registration, with day 0 = registration date. Pregnancy test must be 
obtained 24 hours before treatment with isotretinoin starts. Patients whose 
clinical condition has significantly changed between the time of these tests and 
the initiation of treatment in the judgement of the treating physician, will have a 
repeat chemistry panel prior to the start of treatment.  
 
6.4  
Patients will be enrolled in the mandatory iPLEDGE Program to initiate 
Isotretinoin (cRA) therapy. This program dictates guidelines for pregnancy testing 
and contraception in women of childbearing potential who are treated with cRA 
(please refer to Appendix I for iPLEDGE definition of woman of childbearing 
potential). However, it is anticipated that for the vast majority of patients with 
recurrent malignant glioma, strict adherence to these guidelines would imply 
unacceptable delays in their treatment. For this reason, in women of childbearing 
potential who elect to participate in this protocol, an ”Exception Authorization for 
Oncology Patient” will be requested (Appendix J). This exception authorization 
will allow the patient to start treatment immediately after enrollment in iPLEDGE 
and obtention of a negative pregnancy test. The ”Exception Authorization for 
Oncology Patient” will allow patients to expedite the beginning of therapy by 
eliminating the need for a 1 month delay in the first prescription of cRA. 
 
6.5 
Patients will complete the baseline MD Anderson Symptom Inventory-Brain 
Tumor Module (MDASI-BT) within 14 days (+ 3 working days) of study entry (*). 
 
6.6 
Patients enrolled on the phase II component of the trial will have blood samples 
collected for determination of acetylation status of histones and p21 levels in 
peripheral mononuclear cells before starting treatment (*). 
 
6.7 
If available, unstained paraffin tissue from surgical samples will be obtained. A 
representative paraffin tissue block (at least 5 mm x 5 mm) or 20 unstained 
paraffin slides will be obtained from original surgery, or definitive surgery, or the 
surgery closest to initiation of this clinical trial. Paraffin slides will be used to 
evaluate histone acetylation levels and p21 levels by immunohistochemistry. 
These will be correlated with response. If available, frozen tissue (> 1 g) from 
prior surgeries may also be sent for the same tests in frozen tissue (*).    
            
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* Note: 6.5, 6.6 and 6.7 are optional procedures, and will be obtained if the 
patients gives his or her informed consent. 
 
 
7.0 
ON-STUDY EVALUATION 
 
7.1 
CBC, differential and platelets will be performed weekly (± 3 days) for the first 
cycle. If no significant toxicity is seen, monitoring will be changed to every two 
weeks (± 3 days) during treatment and prior to each new cycle. In addition, all 
patients will have the following tests every 2 weeks (± 3 days)  for the first cycle 
and then every cycle as well as prior to each new cycle if no significant toxicities 
are noted: PT, PTT, INR, total protein, albumin, calcium, phosphorus, 
magnesium, glucose, BUN, creatinine, sodium, potassium, uric acid, total 
bilirubin, alkaline phosphatase, LDH, SGPT, SGOT. All patients will have serum 
amylase, lipase, and lipid panel drawn every 2 cycles of treatment.  Patients may 
also be evaluated with labs at any time clinically indicated. 
 
7.2 
Patients on treatment with enzyme-inducing antiepileptic drugs (phenytoin, 
phenobarbital, carbamazepine)  will be evaluated with anticonvulsant levels as 
considered appropriate by the treating physician. 
 
7.3 
A Gd-DPTA MRI scan shall be done after each 2 cycles of treatment prior to 
initiating the next cycle. MRI scans may also be done at any time clinically 
indicated. 
 
7.4 
Physical and neurologic examinations will be performed after cycle 1 and cycle 
2, and subsequently after each 2 cycles of treatment prior to initiating the next 
cycle. Patients will also be evaluated anytime their clinical situation demands an 
assessment. 
 
7.5 
All patients receiving cRA must be enrolled in the iPLEDGE program (see 
Appendix I). Before starting treatment, an ”Exception Authorization for Oncology 
Patient” will be requested for women of childbearing potential (Appendix J). A 
negative serum pregnancy test will be obtained 24 hours before initiation of 
treatment with cRA. Once treatment has started, pregnancy testing and 
counseling should occur monthly. If pregnancy does occur during cRA treatment, 
the drug must be discontinued immediately and the treating physician notified. 
The treating physician will in turn notify the study chair immediately.  
 
7.6 
The MDASI-BT will be completed at the time of physical and neurologic exam, 
i.e. after cycle 1 and cycle 2, and subsequently after every 2 cycles of 
treatment prior to initiating the next cycle of treatment. (*) 
 
7.7 
All relevant information regarding drug doses, concomitant medications and 
doses, measurable lesions, tumor response, laboratory examinations, and 
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treatment-related toxicities shall be documented in the patient's medical record 
and flow sheets. 
 
7.8 
After treatment on protocol is completed,  patients will be followed for overall 
survival every 3 months, when possible. 
 
7.9 
All patients enrolled in the surgical arm of the phase II component of the trial will 
have tumor tissue and intraoperative blood samples (8ml) collected during 
surgery. Vorinostat will be given at 400 mg once daily for 3 consecutive days 
prior to surgery, with the last dose given on the morning of surgery within 6 hours 
of the tumor removal. Blood samples for acetylation status of histones and p21 
levels in peripheral mononuclear cells will be collected on day 1 before 
(pretreatment), and at 1, 2 and 6 hours after administration of vorinostat. 
 
7.10 Blood samples for acetylation status of histones and p21 levels in peripheral 
mononuclear cells should be collected before (pretreatment) and then 1, 2 and 6 
hours after administration of vorinostat on day 1 of cycle 1, and before and within 
4 hours after administration of vorinostat on day 1 of cycle 2 in patients enrolled 
in arms 1 and 3 of the phase II component (surgical and non-surgical patients). 
Total volume is 144 mL (6 x 24 mL)*.            
 
*Note: 7.6 and 7.10 are optional procedures, and will be obtained if the patients 
gives his or her informed consent.                                                                            
 
 
8.0  
RESPONSE CRITERIA 
 
The primary endpoint is Progression Free Survival (PFS) for determining the "winner" of 
the three regimens tested. Secondary endpoints are a) radiological response to 
treatment, b) the progression free survival at 6 months compared with historical 
controls, and c) overall survival. MRI brain scans will be used to define overall response 
or progression.     
 
8.1 
Disease Evaluability 
8.1.1 Measurable Disease: Bidimensionally measurable lesions with clearly 
defined margins by MRI scan.  
 
8.1.2 Evaluable Disease: Unidimensionally measurable lesions, masses with 
margins not clearly defined. Patients with only this kind of imaging will not be 
allowed to enter this study unless they have recently undergone surgery and 
have histologically proven recurrent disease. 
 
8.1.3 Non-Evaluable Disease: Not Applicable. 
 
8.1.4 Objective Status, To Be Recorded at Each Evaluation: If there are too 
many measurable lesions to measure at each evaluation, choose the largest 
two to be followed before a patient is entered on study.  The remaining 
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lesions will be considered evaluable for the purpose of objective status 
determination.  Unless progression is observed, objective status can only be 
determined when ALL measurable and evaluable sites and lesions are 
assessed. 
 
8.2 
Response Criteria 
8.2.1 Complete Response (CR): Complete disappearance of all measurable and 
evaluable disease.  No new lesions. No evidence of non-evaluable disease. 
All measurable, evaluable and non-evaluable lesions and sites must be 
assessed using the same techniques as baseline. Responders must be on 
none or only maintenance doses of dexamethasone. 
 
8.2.2 Partial Response (PR): Greater than or equal to 50% decrease under 
baseline in the sum of products of perpendicular diameters of all measurable 
lesions. No progression of evaluable disease. No new lesions. All measurable 
and evaluable lesions and sites must be assessed using the same techniques 
as baseline. Responders must be on the same or decreasing doses of 
dexamethasone and have stable or improved neurological exams. 
 
8.2.3 Partial Response, Non-Measurable (PRNM): Not applicable. 
 
8.2.4 Stable/No Response: Does not qualify for CR, PR, or progression. The 
designation of Stable/No Response requires a minimum of 8 weeks duration. 
All measurable and evaluable sites must be assessed using the same 
techniques as baseline. Responders must be on the same or decreasing 
doses of dexamethasone and have stable or improved neurological exams. 
 
8.2.5 Progression: 25% increase in the sum of products of all measurable lesions 
over smallest sum observed (over baseline if no decrease) using the same 
techniques as baseline, OR clear worsening of any evaluable disease, OR 
appearance of any new lesion/site, OR failure to return for evaluation due to 
death or deteriorating condition (unless clearly unrelated to this cancer). 
 
8.2.6   Unknown: Progression has not been documented and one or more 
measurable or evaluable sites have not been assessed. 
8.3 
Note: 
8.3.1 For evaluable disease other than types specified in Section 8.1.2, the only 
objective statuses which apply are CR, stable/no response, progression and 
unknown. 
 
8.3.2 Objective status must stay the same or improve over time until progression 
(unknown excepted). 
 
8.4 
Neurological Exam: Although not used for determining response, it is useful to 
evaluate improvement in the neurologic exam that should coincide with objective 
measurement of tumor size. 
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1 
Normal exam 
 
2 
Improvement from on-study state (patient better) 
 
3 
Same as on-study state (patient same). 
 
4 
Worse than on-study state (patient worse). 
 
8.5 
Performance Status: Patients will be graded according to Karnofsky 
Performance Status (see Appendix G). 
 
8.6 
Progression Free Survival (PFS): From date of registration to the date of first 
observation of progressive disease, non-reversible neurologic progression or 
permanently increased steroid requirement (applies to stable disease only) or 
death due to any cause. Progression Free Survival (PFS)  in patients enrolled in 
the surgical arm will be determined from the date of randomization (i.e. after 
surgery for resection of recurrent tumor), and not from the date of registration in 
the trial. 
 
8.7 
Survival: From date of registration to date of death due to any cause. 
 
8.8 
Steroids:  Steroid dosage will be carefully monitored and recorded during each 
course of therapy and steroid dosage changes will be considered before 
response determinations are made.  
 
8.9 
Unacceptable toxicity: grade 3 or greater toxicity after 3 dose reductions of 
temozolomide or 2 dose reduction of any of the other drugs, or after 1 dose 
reduction if starting dose of vorinostat is 300 mg orally once daily.  
 
 
9.0  
DATA AND SAFETY MONITORING 
 
9.1     Safety Assessments and Toxicity Monitoring:   
 
All patients receiving Vorinostat, Isotretinoin and Temozolomide will be evaluated 
for safety.  The safety parameters include all laboratory tests and hematological 
abnormalities, 
CNS 
observations, 
physical 
examination 
findings, 
and 
spontaneous reports of adverse events reported to the investigator by patients.  
All toxicities encountered during the study will be evaluated according to the NCI 
Common Terminology Criteria (CTCAE) version 3.0 and recorded prior to each 
course of therapy.  Life-threatening toxicities should be reported immediately to 
the Study Chair, Institutional Review Board (IRB), and the FDA. 
 
To provide formal safety monitoring in the Phase II portion of the trial, after 
enrollment of every 10 patients into each of the three arms, we will assess the 
group for toxicity. If dose limiting toxicity as defined in the phase I portion of the 
trial is reached =/> 1/3 of patients despite dose reduction, the arm will stop 
accrual. If dose reduction permits continuation of treatment in these patients, the 
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starting dose levels for the remainder of the patients on the trial will be modified 
to a lower starting dose (-1) level specified in the dose modification section 
 
9.2 
Adverse Event and Reporting Definitions 
 
An adverse event or adverse experience is any untoward medical occurrence in 
a clinical investigation patient who is administered a medicinal product.  An 
adverse event can be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product.  Pre-existing conditions that 
increase in frequency or severity or change in nature during or as a consequence 
of use of a drug are also considered as adverse events.  Adverse events may 
also include pre- or post-treatment complications that occur as a result of 
protocol-mandated procedures (eg, invasive procedures such as biopsies). 
 
An AE does not include: 
 
- Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, 
transfusion).  The condition that leads to the procedure is the adverse event 
 
- Situations where an untoward medical occurrence has not occurred (eg, 
hospitalization for elective surgery, social and/or convenience admissions) 
 
- Overdose of either study drug or concomitant medication without any signs or 
symptoms unless the patient is hospitalized for observation. 
 
The relationship to study drug therapy should be assessed using the 
following definitions: 
 
Not Related:  Evidence exists that the AE has an etiology other than the study 
drug (eg, pre-existing condition, underlying disease, intercurrent illness, or 
concomitant medication). 
 
Possibly/Probably Related:  A temporal relationship exists between the event 
onset and administration of the study drug.  It cannot be readily explained by the 
patient’s clinical state, intercurrent illness or concomitant therapies.  In case of 
cessation or reduction of the dose, the event abates or resolves and reappears 
upon rechallenge.  It should be emphasized that ineffective treatment should not 
be considered as causally related in the context of AE reporting.   
 
A serious adverse event is defined as any adverse drug experience 
occurring at any dose that results in any of the following outcomes:  
 
- Death 
 
- Life-threatening situation (patient is at immediate risk of death) 
 
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-Inpatient hospitalization or prolongation of existing hospitalization (excluding 
those for study therapy, disease-related procedures, palliative or hospice care, 
or placement of an indwelling catheter, unless associated with other serious 
events) 
 
- Persistent or significant disability/incapacity 
 
- Congenital anomaly/birth defect in the offspring of a patient who received study 
drug 
 
- Other: Important medical events that may not result in death, be immediately 
life-threatening, or require hospitalization, may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the patient or 
may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  Examples of such events are: 
 
Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
Blood dyscrasias or convulsions that do not result in hospitalization 
Development of drug dependency or drug abuse 
 
9.3 
Reporting of Serious Adverse Events  
 
All Serious Adverse Events will be reported to the University of Texas M.D. 
Anderson Cancer Center IRB within five working days of knowledge of the 
event. 
.Serious Adverse Events will also be reported to Merck, Sharp and Dohme, 
Corp.,. (Attn: Worldwide Product Safety; FAX 215-993-1220) with copies of all 
serious and/or unexpected adverse experiences, within two working days.  
Investigator will establish and maintain records and make reports to the IRB with 
copies, as described above, to Merck for the following Adverse Experiences: (1) 
all serious, unexpected, adverse events, (2) any significant increase in the 
frequency of serious expected adverse events, and (3) any significant increase in 
the frequency of therapeutic failures.  Additionally, Investigator will report any 
pregnancy occurring in association with use of a Merck Product to Merck, Sharp 
and Dohme, Corp.,. (Attn: Worldwide Product Safety; FAX 215-993-1220).  For 
any serious thromboembolic Adverse Experiences, investigator will fax, at the 
same time as the submission to Merck of the original report, the additional 
information set forth on the attached questionnaire (Appendix L)  In addition, if 
any new information becomes available regarding any Adverse Experience, that 
new information will be submitted to Worldwide Product Safety within two 
working days. 
 
 
10.0  CRITERIA FOR DISCONTINUATION OF TREATMENT 
 
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1. Progressive disease as defined above after one cycle of treatment. (Section  
8.2.5). 
2. The development of unacceptable toxicity.  
3. Patient refusal. 
4. Non-compliance or inability to comply with protocol requirements by patient 
5. Treatment related adverse events not resolved within a 4 weeks rest period or 
requiring more than two dose de-escalations of any drug whichever is earlier. 
 
Patients may remain on treatment as long as disease progression is not observed and 
the patient is not experiencing unacceptable toxicity (see 8.9). Although therapy is 
planned for one year, the patient may remain on treatment beyond this time if both the 
patient and physician agree that further therapy is in the patient’s best interests.                                  
 
 
11.0  STATISTICAL CONSIDERATIONS 
 
11.1 Phase I component  
 
The phase I component will be a non randomized trial in which Arm 1 and Arm 2 
will be opened simultaneously with consecutive patients enrolled alternately to 
each arm, and sequentialy to each dose level. If the MTD is reached earlier in 
one arm, all subsequent patients will be enrolled to the other arm. Once the MTD 
for Arm 1 and Arm 2 is known, Arm 3 will begin accrual. A maximum of 54 
patients will be enrolled in this component of the trial. The MTDs obtained in the 
Phase I component will be used as the Phase II dose in the next component of 
the trial. 
 
 
11.1.1. Arm 1 of the phase I component was to assess the MTD of vorinostat in 
combination with a fixed dosage of cRA as shown in the table below.  As noted 
above in section 5.1.1, the MTD of vorinostat in combination with cRA has been 
established in the current trial. 
 
Level 
Arm 1 
 
Vorinostat 
(mg/day x 14 days) 
cRA 
(mg/m2/day x 21 days) 
0 (starting dose) 
300 
100 
I 
400 
100 
II 
500 
100 
 
 
 
11.1.2.  Arm 2 of the phase I component was aimed at assessing the MTD of 
Carboplatin (CBT) in combination with a fixed dosage of cRA. With the change in 
the combination to temozolomide with isotretinoin, the MTD is already known; 
hence, a phase I trial of this arm will not be needed.  
 
 
 
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11.1.3.  Arm 3 of the phase I component will assess the MTD vorinostat in 
combination with fixed doses of temozolomide + cRA. For temozolomide, the 
Phase II dose determined in Arm 2 will be used. The enrollment will proceed as 
outlined for Arm 1 (cohorts of 3 patients enrolled to each dose level), declaring 
MTD for Temozolomide in combination with vorinostat and cRA once DLT is noted.  
 
 
Level 
Arm 3 
 
Vorinostat 
(mg/day x days 1-7 
and 15-21) 
cRA 
(mg/m2/day 
x 
21 
days) 
Temozolomide 
(mg/m2/day 
on 
days 1-7 &15-21 
-III 
300 
100 
100 
-II 
300 
100 
125 
-I 
400 
100 
125 
0 (starting dose) 400 
100 
150  
I 
500 
100 
150 
 
 
• If the initial cohort of patients at starting dose level 0 do not experience DLT, 
the next cohort of patients will be treated by dose escalation to  level I (with 
increase in the dose of vorinostat). If no patients experience DLT in this 
cohort, 3 more patients will be enrolled to expand this cohort to a total of 6 
patient to confirm that MTD has been achieved. If no DLT is noted or if only 
1/6 patients experience DLT after this expansion of level I, this dose level will 
be declared the MTD and hence the phase II dose.  
• If 2/6 patients have DLT after expansion of dose level I, dose level 0 will be 
declared as the MTD and hence the phase II dose. 
 
• If Dose level 0 exceeds the MTD, lower doses will be studied as noted in the 
table above. If 1/3 patients have DLT at any dose level, the cohort will be 
expanded by 3 more patients. If ≥2/6 patients experience DLT, the MTD will 
be considered as being exceeded and the dose will be de-escalated to the 
next lower dose level and 3 new patients will be enrolled at that level. If none 
or only 1/6 patients experience DLT after dose de-escalation to the lower 
level, this dose level will be declared as the MTD, and will be utilized for the 
phase II component of the study.  
 
 
 
11.2   Phase II component  
 
This is an adaptive randomized phase II trial to compare three treatment arms: a) 
vorinostat + Isotretinoin, b) Temozolomide + Isotretinoin, and c) vorinostat + 
Isotretinoin + Temozolomide, in patients with recurrent GBM.  The primary 
outcome is Progression Free Survival (PFS). Patients will be randomized among 
arms using a Bayesian adaptive algorithm. Technical details of this methodology 
are given in Appendix H. Patients will be randomized fairly among the three arms 
at the start of the trial (for the first 30 patients). Thereafter, as the trial progresses 
and data accrue, the randomization will become unbalanced in favor of the 
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treatment that, on average, has better results in terms of failure time. Therefore, 
each successive patient is more likely to receive the treatment with better results, 
on average. A minimum of 30 and a maximum of 135 patients will be accrued and 
there will be 6 months follow up after the last patient is accrued. Based on an 
anticipated accrual rate between 3 and 5 patients per month, the maximum trial 
accrual period will be between 45 and 27 months.  
 
Patients enrolled in the surgical arm of the phase II component will be randomized 
to one of the three treatment arms after surgery is performed. In surgical patients, 
cycle 1 will be the first cycle of treatment after surgery. PFS in these patients will 
be determined from the date of randomization into the chemotherapy arms (i.e. 
after surgery for tumor resection), and not from the date of registration in the trial. 
 
The tables given below summarize operating characteristics of the design. The 
historical median PFS is 3 months. The tables below assume an accrual rate of 
either 3 or 5 patients per month. The trial will be stopped early and a treatment 
selected as being “better” if the probability that one treatment’s median PFS is 
larger than the other’s PFS exceeds 0.975. If the trial does not stop early and 
the maximum 135 patients are accrued, a treatment is selected as being “better” 
if the probability that one treatment’s median PFS is larger than the other’s PFS 
exceeds 0.85. A treatment arm will be dropped at any point during the trial if the 
probability that the treatment’s median PFS is larger than 3 months is less than 
0.01. The “# of patients treated” row is the average number of patients treated 
on a given arm under the given scenario. When the medians all equal to 3 
months (scenario 1), the probability of selecting one of the three arms (i.e., a 
false positive result) is at most 6% for both accrual rates. The probability of 
selecting the best treatment (i.e., a true positive result) for scenario 4, when the 
medians PFS are 3, 3, and 7 months for the arms, respectively, is 99.5% for the 
accrual rate of 3 patients per month and 99.7% for the accrual rate of 5 patients 
per month. 
 
At each evaluation when a new patient is coming in the study, the data for patients 
who have been followed till that time and not yet progressed are accounted in the 
analysis. 
 
The trial will be conducted using a website developed in the Department of 
Biostatistics at MD Anderson Cancer Center. Through the web interface, the 
users have the ability to randomize patients, update last evaluation date and 
current patient status. When a patient is randomized the calculations are based 
on all available data entered into the website. The results of the randomization 
are displayed to the screen for the user to view. All data is stored in a secure 
SQL server database. 
 
Run Date: Wed May-05-2010 03:46:39 PM  
Trial Design 
Primary endpoint 
Time-To-Event 
Number of arms 
3 
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Minimum patient accrual 
30 
Maximum patient accrual 
135 
Number of patients to randomize fairly 30 
Minimum randomization probability 
0.1 
Tuning parameter 
1 
Additional follow-up 
6 
Goal of study 
Maximize θ 
 
Prior Parameters 
Arm Name Description Prior Parameters (a, b) 
Arm1 
V+A 
(2.009, 3.027) 
Arm2 
T+A 
(2.009, 3.027) 
Arm3 
V+A+T 
(2.009, 3.027) 
 
Stopping Rules 
Suspend accrual to an arm if Pr( θi > max( θj≠ i) | Data ) < PL 
Stop the trial and select an arm as superior if Pr( θi > max( θj≠ i) | Data ) > PU 
At the final analysis select an arm as superior if Pr( θi > max( θj≠ i) | Data ) > PU* 
Suspend accrual to an arm if Pr( θi > θmin) | Data ) < PL* 
Stopping Rule Details  
Arm 
Group 
PL 
PU 
PU* 
θmin PL* 
Arm1 No groups 0.01 0.975 0.85 3 
0.01 
Arm2 No groups 0.01 0.975 0.85 3 
0.01 
Arm3 No groups 0.01 0.975 0.85 3 
0.01 
 
 
SIMULATION PARAMETERS WITH ACCRUAL OF 3 PATIENTS/MONTH 
 
 
Number of patients accrued each month 3 
Number of repetitions 
1000 
Random number generator seed 
123456789 
 
 
 
Scenario 1 
Average Trial Length    49.5 months 
Arm  
True 
Median 
Survival  
Pr( Selected )  
Pr( Selected 
Early ) 
Pr( 
Stopped 
Early ) 
# 
Patients 
(2.5%,97.5%) 
V+A 
3 
0.054 
0.015 
0.082 
43.7 ( 11, 88 ) 
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T+A 
3 
0.051 
0.013 
0.081 
43.8 ( 11, 90 ) 
V+A+T 3 
0.061 
0.015 
0.083 
43.8 ( 11, 89 ) 
 
Scenario 2 
Average Trial Length    43.3 months 
Arm 
 
True 
Median 
Survival  
Pr( Selected )  
Pr( Selected 
Early ) 
Pr( 
Stopped 
Early ) 
# 
Patients 
(2.5%,97.5%) 
V+A 
3 
0.002 
0.002 
0.566 
20.8 ( 10, 49 ) 
T+A 
4 
0.038 
0.018 
0.301 
36.7 ( 10, 89 ) 
V+A+T 5 
0.54 
0.261 
0.026 
59.4 ( 10, 98 ) 
 
Scenario 3 
Average Trial Length    37.5 months 
Arm  
True 
Median 
Survival  
Pr( Selected )  
Pr( Selected 
Early ) 
Pr( 
Stopped 
Early ) 
# 
Patients 
(2.5%,97.5%) 
V+A 
3 
0 
0 
0.918 
14.3 ( 10, 28 ) 
T+A 
5 
0.019 
0.015 
0.528 
31.9 ( 10, 86 ) 
V+A+T 7 
0.758 
0.486 
0.015 
57.6 ( 10, 101 ) 
 
Scenario 4 
Average Trial Length    21.9 months 
Arm  
True 
Median 
Survival  
Pr( Selected )  
Pr( Selected 
Early ) 
Pr( 
Stopped 
Early ) 
# 
Patients 
(2.5%,97.5%) 
V+A 
3 
0 
0 
0.98 
14.4 ( 10, 32 ) 
T+A 
3 
0 
0 
0.979 
14.3 ( 10, 32 ) 
V+A+T 7 
0.995 
0.949 
0 
36 ( 10, 90 ) 
 
Scenario 5 
Average Trial Length    28.6 months 
Arm  
True 
Median 
Survival  
Pr( Selected )  
Pr( Selected 
Early ) 
Pr( 
Stopped 
Early ) 
# 
Patients 
(2.5%,97.5%) 
V+A 
3 
0 
0 
0.935 
14.3 ( 10, 28 ) 
T+A 
4 
0.005 
0.005 
0.833 
20.8 ( 10, 56 ) 
V+A+T 7 
0.96 
0.803 
0.005 
47.5 ( 10, 97 ) 
 
Scenario 6 
Average Trial Length    10.3 months 
Arm  
True 
Pr( Selected )  
Pr( Selected Pr( 
Stopped # 
Patients 
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Median 
Survival  
Early ) 
Early ) 
(2.5%,97.5%) 
V+A 
1 
0.025 
0.001 
0.819 
10.2 ( 10, 13 ) 
T+A 
1 
0.015 
0 
0.802 
10.3 ( 10, 13 ) 
V+A+T 1 
0.012 
0 
0.806 
10.3 ( 10, 13 ) 
 
Run Date: Wed May-05-2010 03:57:33 PM  
Trial Design 
Primary endpoint 
Time-To-Event 
Number of arms 
3 
Minimum patient accrual 
30 
Maximum patient accrual 
135 
Number of patients to randomize fairly 30 
Minimum randomization probability 
0.1 
Tuning parameter 
1 
Additional follow-up 
6 
Goal of study 
Maximize θ 
 
Prior Parameters 
Arm Name Description Prior Parameters (a, b) 
Arm1 
V+A 
(2.009, 3.027) 
Arm2 
T+A 
(2.009, 3.027) 
Arm3 
V+A+T 
(2.009, 3.027) 
 
Stopping Rules 
Suspend accrual to an arm if Pr( θi > max( θj≠ i) | Data ) < PL 
Stop the trial and select an arm as superior if Pr( θi > max( θj≠ i) | Data ) > PU 
At the final analysis select an arm as superior if Pr( θi > max( θj≠ i) | Data ) > PU* 
Suspend accrual to an arm if Pr( θi > θmin) | Data ) < PL* 
Stopping Rule Details  
Arm 
Group 
PL 
PU 
PU* 
θmin PL* 
Arm1 No groups 0.01 0.975 0.85 3 
0.01 
Arm2 No groups 0.01 0.975 0.85 3 
0.01 
Arm3 No groups 0.01 0.975 0.85 3 
0.01 
 
 
SIMULATION PARAMETERS WITH ACCRUAL OF 5 PATIENTS/MONTH 
 
 
Number of patients accrued each month 5 
Number of repetitions 
1000 
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Random number generator seed 
123456789 
 
 
Scenario 1 
Average Trial Length    31.8 months 
Arm  
True 
Median 
Survival  
Pr( Selected )  Pr( Selected 
Early ) 
Pr( 
Stopped 
Early ) 
# 
Patients 
(2.5%,97.5%) 
V+A 
3 
0.04 
0.014 
0.076 
43.8 ( 11, 90 ) 
T+A 
3 
0.046 
0.02 
0.08 
43.7 ( 11, 86 ) 
V+A+T 3 
0.055 
0.018 
0.073 
43.5 ( 10, 88 ) 
 
Scenario 2 
Average Trial Length    28.9 months 
Arm  
True 
Median 
Survival  
Pr( Selected )  Pr( Selected 
Early ) 
Pr( 
Stopped 
Early ) 
# 
Patients 
(2.5%,97.5%) 
V+A 
3 
0.001 
0.001 
0.564 
21.8 ( 10, 49 ) 
T+A 
4 
0.042 
0.021 
0.253 
38.8 ( 10, 87 ) 
V+A+T 5 
0.492 
0.207 
0.023 
61.1 ( 14, 96 ) 
 
Scenario 3 
Average Trial Length    25.1 months 
Arm  
True 
Median 
Survival  
Pr( Selected )  Pr( Selected 
Early ) 
Pr( 
Stopped 
Early ) 
# 
Patients 
(2.5%,97.5%) 
V+A 
3 
0 
0 
0.915 
15.5 ( 10, 33 ) 
T+A 
5 
0.014 
0.012 
0.493 
33.5 ( 10, 83 ) 
V+A+T 7 
0.745 
0.444 
0.012 
60.4 ( 13, 99 ) 
 
Scenario 4 
Average Trial Length    15.3 months 
Arm  
True 
Median 
Survival  
Pr( Selected )  Pr( Selected 
Early ) 
Pr( 
Stopped 
Early ) 
# 
Patients 
(2.5%,97.5%) 
V+A 
3 
0.001 
0.001 
0.968 
16 ( 10, 33 ) 
T+A 
3 
0 
0 
0.973 
15.8 ( 10, 33 ) 
V+A+T 7 
0.997 
0.931 
0.001 
42.4 ( 10, 91 ) 
 
Scenario 5 
Average Trial Length    20.2 months 
Arm  
True 
Pr( Selected )  Pr( Selected Pr( 
Stopped # 
Patients 
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Median 
Survival  
Early ) 
Early ) 
(2.5%,97.5%) 
V+A 
3 
0 
0 
0.944 
15.8 ( 10, 32 ) 
T+A 
4 
0.003 
0.003 
0.803 
23.7 ( 10, 64 ) 
V+A+T 7 
0.949 
0.727 
0.003 
53.2 ( 11, 98 ) 
 
Scenario 6 
Average Trial Length    6.28 months 
Arm  
True 
Median 
Survival  
Pr( Selected )  Pr( Selected 
Early ) 
Pr( 
Stopped 
Early ) 
# 
Patients 
(2.5%,97.5%) 
V+A 
1 
0.02 
0 
0.768 
10.4 ( 10, 14 ) 
T+A 
1 
0.022 
0 
0.762 
10.5 ( 10, 14 ) 
V+A+T 1 
0.024 
0 
0.757 
10.5 ( 10, 15 ) 
 
 (Abbreviations: PFS: Progression free survival; V, vorinostat; A, accutane (isotretinoin); T, 
temozolomide) 
 
Patients’ demographic information at baseline will be analyzed, with data 
summarized in tables listing the number of subjects per treatment group in order 
to assess comparability. The Student t-test or the Wilcoxon rank sum test will be 
used to compare continuous variables between two different patient groups. The 
chi-squared test or the Fisher exact test will be applied to assess the association 
between two categorical variables.   
 
 
 
Time-to-event outcomes, including progression-free survival and overall 
survival, will be estimated using Kaplan-Meier method. The log-rank test will be 
performed to test the difference in time-to-event distributions between patient 
groups. Cox proportional hazards model will be utilized to include multiple 
covariates in the time-to-event analysis.   
 
Toxicity data will be summarized by frequency tables. The association between 
the types and severity of toxicity and the treatment groups will be evaluated. No 
formal statistical testing will be performed on these summary data. 
 
To provide formal safety monitoring in the Phase II portion of the trial, after 
enrollment of every 10 patients into each of the three arms, we will assess the 
group for toxicity. If dose limiting toxicity as defined in the phase I portion of the 
trial is reached =/> 1/3 of patients despite dose reduction, the arm will stop 
accrual. If dose reduction permits continuation of treatment in these patients, the 
starting dose levels for the remainder of the patients on the trial will be modified 
to a lower starting dose (-1) level specified in the dose modification section. 
 
For the efficacy endpoint, intent-to-treat analysis will be applied to the 
randomized and eligible patients. For the toxicity endpoint, as-treated analysis 
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will be used to include any patient who received the treatment – regardless of 
the eligibility nor the duration or dose of the treatment received.  
 
 
11.3 Evaluation of symptom data (MDASI-BT) 
 
The sample size for this trial was based on the primary end point of the study. 
 
Received MDASI-BT forms will be checked versus the timing schedule and 
considered as valid if they fall  within one week of the scheduled assessment. 
Compliance rates will be calculated as the number of received valid forms over the 
number of expected forms. Differences between groups in compliance will be 
tested by use of Fisher’s exact test at every time point. 
 
Estimates of differences in the mean symptom severity and mean symptom 
interference between groups will be estimated in the intent to treat population. All 
patients with at least one valid MDASI-BT will be included in the analyses. MDASI-
BT completed at study registration will be considered baseline. All MDASI-BT data 
received after randomization will be used in the primary analyses. 
 
For the MDASI-BT, differences of at least 2 points will be classified as the 
minimum clinically meaningful change in the symptom severity and symptom 
interference measures. For example, an increase of 2 points or more would mean 
a moderate improvement, whereas a decrease of 2 points or more would be 
interpreted as moderate worsening. For individual symptoms, a rise in a symptom 
score means deterioration, whereas a reduced score means improvement of the 
specific symptom.                                   
 
 
12.0 COMPLIANCE AND DATA MANAGEMENT 
 
12.1  Protocol Compliance: 
 
The attending physician and oncology research nurse must see each patient after 
the first cycle, and subsequently after each 2 cycles of treatment prior to initiating 
the next cycle.  All required interim and pretreatment data should be available and 
the physician must have made a designation as to tumor response and toxicity 
grade. 
 
12.2  Data Entry: 
 
All data will be entered on the computerized Protocol Data Management System 
(PDMS) of the Division of Medicine at MDACC.  Patients must be registered in 
PDMS before a course of therapy can be given.  A brief explanation for required 
but missing data should be recorded as a comment.   
 
12.3  Accuracy of Data Collection: 
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A group consisting of the study chairman, the department chairman, the deputy 
chairman and an faculty member from the neuroradiology department will be the 
final arbiter of response or toxicity should a difference of opinion exist.  The study 
chair will have the deciding vote in case of a tie.  
 
Any life-threatening and/or unexpected and serious (grade 3 or 4) toxicity will be 
reported within 5 working days to the Study Chairman who, in turn, must notify the 
Surveillance Committee and the sponsoring agencies (See Appendix A). 
 
 
13.0 REFERENCES 
 
1.  
Stupp, R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al. 
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N 
Engl J Med. 2005;352:987-96. 
 
2.  
Yung WK, Kyritsis AP, Gleason MJ, Levin VA. Treatment of recurrent malignant 
gliomas with high-dose 13-cis-retinoic acid. Clin Cancer Res. 1996;2:1931-5. 
 
3.  
See SJ, Levin VA, Yung WK, Hess KR, Groves MD. 13-cis-retinoic acid in the 
treatment of recurrent glioblastoma multiforme. Neuro-oncol. 2004;6:253-8. 
 
4.  
Jaeckle KA, Hess KR, Yung WK, Greenberg H, Fine H, Schiff D et al. Phase II 
evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent 
and progressive malignant glioma: a North American Brain Tumor Consortium 
study. J Clin Oncol. 2003;21:2305-11. 
 
5.  
Lippman SM, Kessler JF, Al-Sarraf M, Alberts DS, Itri LM, Mattox D, Von Hoff DD, 
Loescher L, Meisken FL. Treatment of advanced squamous cell carcinoma of the 
head and neck with isotretinoin: a phase II randomized trial. Invest New Drugs. 
1998; 6:51-6. 
 
6.  
Marks, P., R.A. Rifkind, V.M. Richon, et al. Histone deacetylases and cancer: 
causes and therapies. Nat Rev Cancer. 2001;1:194-202. 
 
7.  
Investigator's Brochure – Vorinostat. Merck and Co., Inc. 6-23-06.  
 
 8.  Kelly, W.K., V.M. Richon, O. O'Connor, et al. Phase I Clinical Trial of Histone 
Deacetylase 
Inhibitor: 
Suberoylanilide 
Hydroxamic 
Acid 
Administered 
Intravenously.  Clin Cancer Res. 2003; 9:3578-3588. 
 
9.  
Garcia-Manero, G.; Issa, J.P.; Cortes, J.; Koller, C.; O’brien, S. et al. Phase I study 
of oral suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, in patients 
with advanced leukemia or myelodysplastic syndrome. Proc ASCO. 2004. 
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10.  Richardson, P.; Schlossman, R.; Mitsiades, C.S.; Munshi, N.; Colson, K. et al.  
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