Vorinostat and Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00673153
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 31
• Locations: 4
• Arm: 1
• Patients Per Site: 7.8

Study Details

Study Description

Brief Summary

RATIONALE: Vorinostat may stop the growth of cancer cells by interfering with various proteins needed for cell growth. Monoclonal antibodies, such as gemtuzumab ozogamicin (GO), can block cancer growth in different ways. GO finds cancer cells and helps kill them by carrying a cancer-killing substance to them. Giving vorinostat together with gemtuzumab ozogamicin may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving vorinostat together with gemtuzumab ozogamicin works in treating older patients with previously untreated acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Untreated Adult Acute Myeloid Leukemia	Drug: gemtuzumab ozogamicin; Drug: vorinostat; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the CR/CRi rate after treatment with vorinostat plus GO. (Good risk group)
2. To determine the 30-day survival after treatment with vorinostat plus GO. (Poor risk group)

SECONDARY OBJECTIVES:

1. To estimate the frequency and severity of regimen-associated toxicities, along with 30-day survival after start of treatment with vorinostat plus GO. (Good risk group) II. To determine the CR/CRi rate after treatment with vorinostat plus GO, and estimate the frequency and severity of regimen-associated toxicities. (Poor risk group) III. To investigate the relapse-free survival of patients who achieve CR/CRi and receive maintenance therapy on this study.

2. To define cellular factors associated with clinical response to GO/vorinostat and determine the mechanisms underlying the synergistic effect between GO and vorinostat on primary AML cells (in vitro correlative and mechanistic studies).

OUTLINE:

REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to 3 courses.

CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8.

MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses.

All treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Vorinostat (Suberoylanilide Hydroxamic Acid or SAHA; Zolinza™) in Combination With Gemtuzumab Ozogamicin (Mylotarg™) as Induction and Post-Remission Therapy in Older Patients With Previously Untreated Non-M3 Acute Myeloid Leukemia
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Aug 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Arm I REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to 3 courses. . CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses.

Drug: gemtuzumab ozogamicin; Given IV; Other Names: Calicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody CDP-771 CMA-676 hP67.6-Calicheamicin Mylotarg WAY-CMA-676 ; Drug: vorinostat; Given orally; Other Names: L-001079038 SAHA suberoylanilide hydroxamic acid Zolinza ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Number of Participants Achieving CR or CRi With Induction Therapy (Good-risk Group) [after completion of induction therapy, administered every 21-42 days for up to two courses]

2. Number of Participants Alive at Day 30 (Poor-risk Group) [At day 30]

Secondary Outcome Measures

1. Relapse-free Survival (Good- and Poor-risk Group) [At relapse]

2. Number of Participants Achieving CR or CRi With Induction Therapy (Poor-risk Group) [after completion of induction therapy, administered every 21-42 days for up to two courses]

3. Number of Participants Alive at Day 30 (Good-risk Group) [At day 30]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Morphological diagnosis of AML other then acute promyelocytic leukemia (FAB M3) according to WHO diagnostic criteria; diagnosis of AML must be based on bone marrow or peripheral blood studies obtained within 28 days prior to study registration or start of hydroxyurea (for patients presenting with WBC >= 10,000/uL), and no potentially anti-leukemic therapy (with the exception of hydroxyurea) must have been given between AML diagnosis and study registration; a bone marrow biopsy is not routinely required but should be obtained if the aspirate is dilute, hypocellular, or inaspirable; outside bone marrows performed within the stipulated time period are acceptable as long as the slides are reviewed at a study institution

• Cytogenetic analysis on bone marrow or peripheral blood specimen is available; based on the result from the first interim analysis, patients stratified into the good-risk group are only eligible if their AML has favorable cytogenetics (core-binding factor AML) or has a normal karyotype; patients stratified into the poor-risk group are eligible independent of the cytogenetic analysis

• Pretreatment bone marrow and peripheral blood specimens for correlative studies are available; if bone marrow was performed at an outside facility, submission of peripheral blood only is acceptable as long as the peripheral blast count is > 5,000/uL and > 50% of total WBC

• Patients with a history of antecedent MDS are eligible, if prior treatment did not include intensive chemotherapy; patients may have received hematopoietic growth factors, thalidomide/lenalidomide, 5-azacytidine/decitabine, arsenic trioxide, signal transduction inhibitors, or low dose cytarabine (< 100 mg/m2/day) for treatment of MDS; patients must be off prior therapy for MDS at least 30 days prior to study registration, and all non-hematologic toxicities must have resolved to < grade 2

• ECOG/WHO/Zubrod performance status of 0-3

• Bilirubin =< 2.5 x Institutional Upper Limit of Normal (IULN) unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis (assessed within 14 days prior to registration)

• SGOT (AST) and SPGT (ALT) =< 1.5 x IULN unless elevation is thought to be due to hepatic infiltration by AML (assessed within 14 days prior to registration)

• Serum creatinine =< 1.5 x IULN (assessed within 14 days prior to registration)

• Left ventricular ejection fraction >= 40% and no clinical evidence of congestive heart failure (assessed within 28 days prior to registration, e.g. by MUGA scan or echocardiography)

• Men of reproductive potential must use an effective contraceptive method throughout the study and for a period of at least 3 months after the study

• Women must be postmenopausal; a postmenopausal woman is defined as a woman who has experienced amenorrhea > 12 consecutive months or a woman on hormone replacement therapy with documented FSH level > 35 mIU/mL (women of childbearing potential must have a pregnancy test within 28 days prior to registration, and must use an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 3 months after the study)

• Provide signed written informed consent

• Willingness to undergo bone marrow examination on day 8 of first induction cycle

• WBC < 10,000/uL (patients with WBC >= 10,000/uL must undergo cytoreduction with hydroxyurea prior to enrollment and will not be enrolled if the WBC remains >= 10,000/uL (of note, patients with symptoms/signs of hyperleukocytosis or WBC > 100,000/uL can be treated with leukapheresis prior to enrollment)

Exclusion Criteria:

• Diagnosis of another malignancy, unless the patient was diagnosed at least 2 years earlier and has been disease-free for at least 6 months following the completion of curative intent therapy; there should be no plan to begin therapy for the prior malignancy at the time of study registration; prior treatment with AML induction-type chemotherapy is not allowed (note the following exceptions: patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed; patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen [PSA] values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed; concurrent hormonal therapy is allowed)

• Myeloid blast crisis of chronic myelogenous leukemia (CML)

• Prior systemic chemotherapy for AML with the exception of hydroxyurea

• Prior treatment with AML induction-type chemotherapy, GO, HDAC inhibitors, or high dose chemotherapy with hematopoietic stem cell support

• Treatment with HDAC inhibitors during the last 3 years prior to registration, including the use of valproic acid for seizure activity or other purposes

• Known hypersensitivity to hydroxyurea, GO, or vorinostat

• Clinical evidence suggestive of central nervous system (CNS) involvement with leukemia unless a lumbar puncture confirms the absence of leukemic blasts in the cerebrospinal fluid (CSF)

• Prior positive test for the human immunodeficiency virus (HIV)

• Breastfeeding

• Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University	Stanford	California	United States	94305
2	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
3	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
4	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Roland Walter, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Roland Walter, Principal Investigator, Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00673153
• Other Study ID Numbers: 2200.00; NCI-2010-00401
• First Posted: May 7, 2008
• Last Update Posted: Jun 1, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Vorinostat; Gemtuzumab; Calicheamicins

Study Results

Participant Flow

Arm/Group Title	Arm I
Arm/Group Description	REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to 3 courses. . CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses. gemtuzumab ozogamicin: Given IV vorinostat: Given orally laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	31
COMPLETED	30
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Arm I
Arm/Group Description	REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to 3 courses. . CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses. gemtuzumab ozogamicin: Given IV vorinostat: Given orally laboratory biomarker analysis: Correlative studies
Overall Participants	31
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	72
Sex: Female, Male (Count of Participants)
Female	11 35.5%
Male	20 64.5%
Region of Enrollment (participants) [Number]
United States	31 100%
Risk Group (Count of Participants)
Poor-risk Group	10 32.3%
Good-risk Group	21 67.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Achieving CR or CRi With Induction Therapy (Good-risk Group)
Time Frame	after completion of induction therapy, administered every 21-42 days for up to two courses

Outcome Measure Data

Analysis Population Description

Good-risk Group: aged 60-69 years with performance status 0-3, or aged ≥70 years and performance status 0-1

Arm/Group Title	Arm I
Arm/Group Description	REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to 3 courses. . CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses. gemtuzumab ozogamicin: Given IV vorinostat: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	21
Count of Participants [Participants]	6 19.4%

2. Primary Outcome

Title	Number of Participants Alive at Day 30 (Poor-risk Group)
Time Frame	At day 30

Outcome Measure Data

Analysis Population Description

Poor-risk Group: patients aged ≥70 years and performance status 2-3

Arm/Group Title	Arm I
Arm/Group Description	REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to 3 courses. . CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses. gemtuzumab ozogamicin: Given IV vorinostat: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	10
Count of Participants [Participants]	8 25.8%

3. Secondary Outcome

Title	Relapse-free Survival (Good- and Poor-risk Group)
Time Frame	At relapse

Outcome Measure Data

Analysis Population Description

Poor-risk Group: patients aged ≥70 years and performance status 2-3; Good-risk Group: aged 60-69 years with performance status 0-3, or aged ≥70 years and performance status 0-1

Arm/Group Title	Arm I
Arm/Group Description	REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to 3 courses. . CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses. gemtuzumab ozogamicin: Given IV vorinostat: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	31
Count of Participants [Participants]	7 22.6%

4. Secondary Outcome

Title	Number of Participants Achieving CR or CRi With Induction Therapy (Poor-risk Group)
Time Frame	after completion of induction therapy, administered every 21-42 days for up to two courses

Outcome Measure Data

Analysis Population Description

Poor-risk Group: patients aged ≥70 years and performance status 2-3

Arm/Group Title	Arm I
Arm/Group Description	REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to 3 courses. . CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses. gemtuzumab ozogamicin: Given IV vorinostat: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	10
Count of Participants [Participants]	1 3.2%

5. Secondary Outcome

Title	Number of Participants Alive at Day 30 (Good-risk Group)
Time Frame	At day 30

Outcome Measure Data

Analysis Population Description

Good-risk Group: aged 60-69 years with performance status 0-3, or aged ≥70 years and performance status 0-1

Arm/Group Title	Arm I
Arm/Group Description	REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to 3 courses. . CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses. gemtuzumab ozogamicin: Given IV vorinostat: Given orally laboratory biomarker analysis: Correlative studies
Measure Participants	21
Count of Participants [Participants]	20 64.5%

Adverse Events

Arm/Group Title	Arm I
Arm/Group Description	REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to 3 courses. . CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin IV over 2 hours on day 8. MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment repeats every 28 days for 4 courses. gemtuzumab ozogamicin: Given IV vorinostat: Given orally laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Arm I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	12/31 (38.7%)
Blood and lymphatic system disorders
Epistaxis	1/31 (3.2%)	1
Gastrointestinal disorders
GI Bleed	1/31 (3.2%)	1
General disorders
Death	4/31 (12.9%)	4
Infections and infestations
Pneumonia	2/31 (6.5%)	2
Neutropenic Fever	5/31 (16.1%)	5
Septic Shock	1/31 (3.2%)	1
E-coli Infection	1/31 (3.2%)	1
Injury, poisoning and procedural complications
Fall	1/31 (3.2%)	1
Skin and subcutaneous tissue disorders
Perirectal cellulitis	1/31 (3.2%)	1
Surgical and medical procedures
Bleeding at PICC site	1/31 (3.2%)	1
Other (Not Including Serious) Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	29/31 (93.5%)
Blood and lymphatic system disorders
Neutropenia	19/31 (61.3%)	26
Thrombocytopenia	18/31 (58.1%)	22
Anemia	10/31 (32.3%)	10
Hypokalemia	1/31 (3.2%)	1
White blood cell decreased	2/31 (6.5%)	3
Hemorrhage, post bone marrow	1/31 (3.2%)	1
Cardiac disorders
Cardiac arrhythmia	2/31 (6.5%)	5
Heart Failure	1/31 (3.2%)	2
Non-ST-elevation myocardial infarction	1/31 (3.2%)	1
Eye disorders
Blurred Vision	1/31 (3.2%)	1
Gastrointestinal disorders
Nausea	2/31 (6.5%)	2
Diarrhea	3/31 (9.7%)	4
Gingival bleeding	1/31 (3.2%)	2
Hemorrhoidal hemorrhage	1/31 (3.2%)	1
Constipation	1/31 (3.2%)	2
Gastrointestinal Bleed	2/31 (6.5%)	2
Appendix Fistula	1/31 (3.2%)	1
General disorders
Chills	3/31 (9.7%)	3
Fatigue	3/31 (9.7%)	3
Edema/Swelling	2/31 (6.5%)	2
Infusion related reaction	1/31 (3.2%)	1
Malaise	1/31 (3.2%)	1
Immune system disorders
Streptococcus salivarius	1/31 (3.2%)	1
Infections and infestations
Neutropenic Fever	7/31 (22.6%)	14
Sepsis	1/31 (3.2%)	1
Bacteremia	3/31 (9.7%)	3
Investigations
Weight loss	2/31 (6.5%)	2
Creatinine increased	3/31 (9.7%)	3
Increased lactate dehydrogenase	1/31 (3.2%)	1
Metabolism and nutrition disorders
Anorexia	2/31 (6.5%)	2
Hyperglycemia	1/31 (3.2%)	1
Diaphoresis	1/31 (3.2%)	1
Musculoskeletal and connective tissue disorders
Chest pain	2/31 (6.5%)	3
Muscle Weakness	2/31 (6.5%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pulmonary Nodules	1/31 (3.2%)	1
Nervous system disorders
Headache	1/31 (3.2%)	1
Psychiatric disorders
Confusion	2/31 (6.5%)	2
Renal and urinary disorders
Increased urinary frequency	1/31 (3.2%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/31 (3.2%)	1
Pneumonia	4/31 (12.9%)	4
Dyspnea	2/31 (6.5%)	2
Epistaxis	3/31 (9.7%)	3
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	1/31 (3.2%)	1
Vascular disorders
Hematoma, scalp	1/31 (3.2%)	1
Orthostatic hypotension	2/31 (6.5%)	2
Hypertension	1/31 (3.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted to the sponsor for review. The sponsor CAN require changes to the communication and CAN extend the embargo.