Carboplatin and Etoposide in Combination With Vorinostat for Patients With Extensive Stage Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT00702962
• Recruitment Status: Terminated
• First Posted: June 20, 2008
• Results First Posted: October 15, 2018
• Last Update Posted: October 22, 2018
• Sponsor: Milton S. Hershey Medical Center
• Collaborators: Merck Sharp & Dohme Corp.; University of Pennsylvania
• Information provided by (Responsible Party): Chandra P. Belani, Milton S. Hershey Medical Center

• Study Type: Interventional
• Study Design: Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Small Cell Lung Cancer
• Intervention: Drug: Vorinostat, Carboplatin, Etoposide
• Enrollment: 8

Participant Flow

Recruitment Details	Open to accrual 09/2008 as Phase I study. Three participants treated with dose level 1. Similar NCI-CTEP Phase I trial (NCI 8703) established the maximum tolerated dose (MTD) for the study drug. This study was amended to Phase II using the NCI established dose. One participant treated on Phase II. Closed to accrual 01/2012 due to low enrollment.
Pre-assignment Details	Eight patients total were consented (i.e. "enrolled"). Three of the 8 were determined to be ineligible upon screening. One of the 8 was eligible but subsequently declined participation soon after signing consent. Four (4) of 8 enrolled went to active treatment ("started"). Of these 4, 3 participated in Phase I and 1 participated in Phase II.

Arm/Group Title	Phase II Portion - Vorinostat 300mg	Phase I Portion - Vorinostat 200mg
Arm/Group Description	Phase 2 is to determine progression free survival among patients with extensive disease SCLC receiving carboplatin plus etoposide with vorinostat.Vorinostat, Carboplatin, Etoposide, SAHA SAHA: Once the recommended phase II dose has been established and additional 15 patients will be enrolled. Days 1-4 Vorinostat recommended phase II dose po QD;Day 3 Carboplatin 6 AUC; Days 1,2,3 Etoposide 100 mg/m2. Treatment cycles will be repeated every 3 weeks. A maximum of 4 cycles will be administered to each patient. An additional 35 patients on the phase II portion of the trial will be required to achieve the outlined objectives.	Vorinostat 200 mg PO QD D1-14; Carbo 6 (AUC) D3; Etoposide 100 mg/m2 D1,2,3 Vorinostat, Carboplatin, Etoposide, SAHA. Vorinostat, Carboplatin, Etoposide: Sequential cohorts of 3-6 patients will be entered to the following dose levels: Level 1 - Days 1-14: Vorinostat 200 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2. Level 2 - Days 1-14: Vorinostat 300 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2; Level 3: Days 1-14: Vorinostat 400 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2. Treatment cycles will be repeated every 3 weeks. A maximum of 4 cycles will be administered to each patient. Phase I was prematurely closed as an NCI study established the MTD. This study proceeded to Phase II soon after the first participant was enrolled at Dose Level 2 (300mg).
Period Title: Overall Study
Started	1 [1]	3 [2]
Completed	0 [3]	2 [4]
Not Completed	1	1
Reason Not Completed
Progressive disease	0	1
Hospitalized for other health disorder	1	0
[1] One initiated treatment. Milestones not achieved due to premature closing due to low accrual.; [2] Three treated. Milestone not met as Phase I closed prematurely as NCI research established the MTD.; [3] The one participant off treatment after 2 doses due to concurrent health disorder.; [4] Two completed all required cycles. One experienced progressive disease after 2 cycles

Baseline Characteristics

Arm/Group Title		PHASE I: Vorinostat 200mg Carbo 6 (AUC)	PHASE II: Vorinostat 300mg Carbo 6 (AUC)	Total
Arm/Group Description		Phase I portion: To determine MTD of Vorinostat when used in combination with other chemotherapy. Start at Vorinostat 200 mg PO QD D1-14; Carbo 6 (AUC) D3; Etoposide 100 mg/m2 D1,2,3; Vorinostat, Carboplatin, Etoposide, SAHA Vorinostat, Carboplatin, Etoposide: Sequential cohorts of 3-6 patients will be entered to the following dose levels: Level 1 - Days 1-14: Vorinostat 200 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2. Level 2 - Days 1-14: Vorinostat 300 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2; Level 3: Days 1-14: Vorinostat 400 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2. Treatment cycles will be repeated every 3 weeks. A maximum of 4 cycles will be administered to each patient.	Phase II portion: To determine progression free survival among patients with extensive disease SCLC receiving carboplatin plus etoposide with fixed dose Vorinostat. (Vorinostat, Carboplatin, Etoposide, SAHA) SAHA: Once the recommended phase II dose has been established and additional 15 patients will be enrolled. Days 1-4 Vorinostat recommended phase II dose po QD;Day 3 Carboplatin 6 AUC; Days 1,2,3 Etoposide 100 mg/m2. Treatment cycles will be repeated every 3 weeks. A maximum of 4 cycles will be administered to each patient. An additional 35 patients on the phase II portion of the trial will be required to achieve the outlined objectives.	Total of all reporting groups
Overall Number of Baseline Participants		3	1	4
Baseline Analysis Population Description		The first Phase I portion enrolled the first 3 participants at dose level 1 (Vorinostat 200 mg). Phase I closed prematurely as the recommended dose was established in other national clinical trials. Phase II used the established dose of Vorinostat 300 mg. Phase II closed prematurely due to low accrual.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants	1 participants	4 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	2 66.7%	1 100.0%	3 75.0%
	>=65 years	1 33.3%	0 0.0%	1 25.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	3 participants	1 participants	4 participants
		64.3 (10.8)	70 (0)	65.8 (9.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants	1 participants	4 participants
	Female	1 33.3%	0 0.0%	1 25.0%
	Male	2 66.7%	1 100.0%	3 75.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	3 participants	1 participants	4 participants
		3 100.0%	1 100.0%	4 100.0%

Outcome Measures

1. Primary Outcome

Title	Assess Maximum Tolerated Dose of Vorinostat When Combined With Carboplatin and Etoposide of Patients With Extensive Disease SCLC
Description	To estimate the maximum tolerated dose of vorinostat using a traditional dose escalation schedule ("3 + 3 design). MTD is determined by assessing for specific predefined dose limiting toxicities. A starting dose of vorinostat 200mg was combined with carboplatin and etoposide. Dose escalation went in increments of 100mg (i.e. 300mg, 400mg).
Time Frame	2 years, not analyzed

Outcome Measure Data

Analysis Population Description

The first three participants enrolled were treated at dose level 1 (vorinostat 200 mg). Phase I protocol closed prematurely with no additional subjects enrolled. No analysis due to premature closure.

Arm/Group Title	Phase I Dose Escalation of Vorinostat (200-400mg)
Arm/Group Description:	Vorinostat 200 mg PO QD D1-14; Carbo 6 (AUC) D3; Etoposide 100 mg/m2 D1,2,3 Vorinostat, Carboplatin, Etoposide, SAHA Vorinostat, Carboplatin, Etoposide: Sequential cohorts of 3-6 patients will be entered to the following dose levels: Level 1 - Days 1-14: Vorinostat 200 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2. Level 2 - Days 1-14: Vorinostat 300 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2; Level 3: Days 1-14: Vorinostat 400 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2. Treatment cycles will be repeated every 3 weeks. A maximum of 4 cycles will be administered to each patient.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

2. Secondary Outcome

Title	To Evaluate Overall Survival of Patients With Extensive Disease SCLC Receiving Carboplatin, Etoposide, and a Fixed Dose (300mg) of Vorinostat
Description	For the purpose of this study, overall survival is defined as the percentage of participants who are alive at two years post initiation of study treatment.
Time Frame	2 years, not analyzed

Outcome Measure Data

Analysis Population Description

One participant enrolled on Phase II. Off treatment and off study prematurely due to concurrent health disorders.

Arm/Group Title	Phase II Vorinostat 300mg With Carboplatin and Etoposide
Arm/Group Description:	Participants with extensive disease SCLC receiving carboplatin, Etoposide, and a fixed dose (300mg) of vorinostat. Days 1-4 Vorinostat 300mg po QD; Day 3 Carboplatin 6 AUC; Days 1,2,3 Etoposide 100 mg/m2. Treatment cycles will be repeated every 3 weeks. A maximum of 4 cycles will be administered to each participant.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

3. Secondary Outcome

Title	Evaluate Objective Response Rate Among Patients With Extensive Disease SCLC Receiving Carboplatin and Etoposide With a Fixed Dose of Vorinostat.
Description	Eligibility limits the study population to those who have measurable disease pre-treatment. This secondary outcome measure was intended to objectively evaluate disease response and survival rate in recipients of the investigational medication regimen. Disease response was performed using standard diagnostic imaging. Tumor markers and cytology may be used to support the imaging results. Objective response rate was defined as progression-free survival (PFS) among treatment recipients. PFS, is defined as time (in months) from entry to clinical evidence of disease progression or death without progression. The clinical trial closed prematurely due to low accrual. For this reason, an analysis of this secondary objective would not be meaningful. No analysis done.
Time Frame	2 years, not analyzed

Outcome Measure Data

Analysis Population Description

One participant enrolled and treated in the Phase II portion. Participant rendered off treatment and off study prior to completion due to concurrent health disorders. The clinical trial closed prematurely due to low accrual. For this reason, an analysis of this secondary objective would not be meaningful. No analysis done.

Arm/Group Title	Phase II Vorinostat 300mg With Carboplatin and Etoposide
Arm/Group Description:	Participants with extensive disease small cell lung cancer who receive carboplatin plus etoposide with a fixed dose of vorinostat. Participants will receive: Days 1-4 Vorinostat recommended phase II dose po QD; Day 3 Carboplatin 6 AUC; Days 1,2,3 Etoposide 100 mg/m2. Treatment cycles will be repeated every 3 weeks. A maximum of 4 cycles will be administered to each participant.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

4. Secondary Outcome

Title	To Assess the Safety Profile and Define the Toxicities of Using a Fixed Dose (300mg) of Vorinostat With Carboplatin and Etoposide
Description	Evaluation of resultant adverse events that occurred with participants with extensive disease SCLC after initiating treatment using a fixed dose of vorinostat in combination with carboplatin and etoposide.
Time Frame	2 years, not analyzed

Outcome Measure Data

Analysis Population Description

One participant enrolled in the Phase II portion and discontinued treatment prematurely due to concurrent health issues and hospitalization. No unanticipated adverse events occurred while on study. The study closed prematurely due to low accrual. No analysis conducted.

Arm/Group Title	Phase II Vorinostat 300mg With Carboplatin and Etoposide
Arm/Group Description:	Participants with extensive disease SCLC receiving carboplatin, Etoposide, and a fixed dose (300mg) of vorinostat. Participants will receive on Days 1-4 Vorinostat 300mg po QD; Day 3 Carboplatin 6 AUC; Days 1,2,3 Etoposide 100 mg/m2. Treatment cycles will be repeated every 3 weeks. A maximum of 4 cycles will be administered to each participant.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	The time period for adverse event collection is from the time of consent to 30 days after last treatment cycle.
Adverse Event Reporting Description	Per clinicaltrials.gov standard definitions
Arm/Group Title	Phase II: Vorinostat 300mg With Carboplatin and Etoposide		Phase I: Determine MTD Vorinostat (200mg-400mg)
Arm/Group Description	Phase 2 objective is to determine progression free survival among patients with extensive disease SCLC receiving carboplatin plus etoposide using an established dose of Vorinostat. Participants in Phase II received a "cycle" consisting of the NCI recommended Vorinostat dose with Carboplatin 6 AUC and Etoposide 100 mg/m2. Treatment cycles were repeated every 3 weeks. A maximum of 4 cycles were administered. A total of 35 participants were required for Phase II analysis. The Phase II study closed prematurely due to low accrual. Analysis of the primary and secondary objectives was not possible due to inadequate sample size.		The original purpose of the Phase I portion was to establish the MTD of Vorinostat when provided with other chemotherapy (Carboplatin and Etoposide). Initial dose at 200mg, then 300, to a max of 400 mg. The first cohort at 200 mg did well with no dose limiting toxicities. After the enrollment of the 1st participant into cohort 2, the Phase I study was prematurely closed as concurrent NCI publications had established appropriate dose levels. The phase I portion was closed after the first 3 participants. Analysis of the objectives is not applicable due to premature closing.
All-Cause Mortality
	Phase II: Vorinostat 300mg With Carboplatin and Etoposide		Phase I: Determine MTD Vorinostat (200mg-400mg)
	Affected / at Risk (%)		Affected / at Risk (%)
Total	1/1 (100.00%)		3/3 (100.00%)
Serious Adverse Events
	Phase II: Vorinostat 300mg With Carboplatin and Etoposide		Phase I: Determine MTD Vorinostat (200mg-400mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0.00%)		1/3 (33.33%)
Vascular disorders
Thrombophlebitis † 1 [1]	0/1 (0.00%)	0	1/3 (33.33%)	1
1 Term from vocabulary, NCI CTC V3; † Indicates events were collected by systematic assessment; [1] Phlebitis (including superficial thrombosis); Hospitalization for Thrombophlebitis
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Phase II: Vorinostat 300mg With Carboplatin and Etoposide		Phase I: Determine MTD Vorinostat (200mg-400mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100.00%)		3/3 (100.00%)
Blood and lymphatic system disorders
Leukopenia † 1 [1]	1/1 (100.00%)	1	3/3 (100.00%)	10
Neutropenia † 2 [2]	1/1 (100.00%)	1	3/3 (100.00%)	11
Thrombocytopenia † 1 [3]	1/1 (100.00%)	1	2/3 (66.67%)	10
Anemia † 1 [4]	0/1 (0.00%)	0	3/3 (100.00%)	4
Gastrointestinal disorders
Nausea † 1 [5]	0/1 (0.00%)	0	3/3 (100.00%)	5
Anorexia † 1 [6]	1/1 (100.00%)	1	0/3 (0.00%)	0
Dry mouth † 1 [7]	0/1 (0.00%)	0	1/3 (33.33%)	1
Pain - Throat/pharynx/larynx † 1	0/1 (0.00%)	0	1/3 (33.33%)	2
General disorders
Fatigue † 1 [8]	0/1 (0.00%)	0	3/3 (100.00%)	9
Facial flushing † 1 [9]	0/1 (0.00%)	0	1/3 (33.33%)	3
Insomnia † 1 [10]	0/1 (0.00%)	0	2/3 (66.67%)	4
Fever without neutropenia † 1 [11]	0/1 (0.00%)	0	1/3 (33.33%)	1
Hepatobiliary disorders
Hyperbilirubinemia † 1 [12]	0/1 (0.00%)	0	1/3 (33.33%)	1
Infections and infestations
Vaginal Candidiasis † 1 [13]	0/1 (0.00%)	0	1/3 (33.33%)	3
Metabolism and nutrition disorders
Hyperglycemia † 1 [14]	0/1 (0.00%)	0	1/3 (33.33%)	3
Alkaline phosphatase, elevated † 1 [15]	0/1 (0.00%)	0	3/3 (100.00%)	3
Alanine aminotransferase (ALT) elevation † 1 [16]	0/1 (0.00%)	0	1/3 (33.33%)	1
Hypocalcemia † 1 [17]	0/1 (0.00%)	0	1/3 (33.33%)	1
Hypermagnesemia † 1 [18]	0/1 (0.00%)	0	1/3 (33.33%)	1
Hypokalemia † 1 [19]	0/1 (0.00%)	0	1/3 (33.33%)	1
Hyponatremia † 1 [20]	0/1 (0.00%)	0	1/3 (33.33%)	3
Nervous system disorders
Dizziness † 1	0/1 (0.00%)	0	2/3 (66.67%)	2
Restlessness with irritibility † 1 [21]	0/1 (0.00%)	0	1/3 (33.33%)	1
Anxiety † 1 [22]	0/1 (0.00%)	0	1/3 (33.33%)	1
Abnormal dreams † 1	0/1 (0.00%)	0	1/3 (33.33%)	1
Back pain † 1	0/1 (0.00%)	0	1/3 (33.33%)	2
Pain, extremity/limb † 1	0/1 (0.00%)	0	1/3 (33.33%)	1
Headache † 1	0/1 (0.00%)	0	1/3 (33.33%)	1
Respiratory, thoracic and mediastinal disorders
Cough † 1 [23]	0/1 (0.00%)	0	1/3 (33.33%)	1
Hiccoughs † 1 [24]	0/1 (0.00%)	0	1/3 (33.33%)	2
Skin and subcutaneous tissue disorders
Erythema, skin † 1 [25]	0/1 (0.00%)	0	2/3 (66.67%)	2
Cellulitis † 1 [26]	0/1 (0.00%)	0	1/3 (33.33%)	1
Ulceration, vaginal † 1 [27]	0/1 (0.00%)	0	1/3 (33.33%)	1
1 Term from vocabulary, NCI CTC V3; 2 Term from vocabulary, NCI CTC V4; † Indicates events were collected by systematic assessment; [1] Leukocytes (total WBC); [2] Neutrophils/granulocytes (ANC/AGC); [3] Platelets, low; [4] Hemoglobin, Low; [5] Nausea; [6] Decreased appetite; [7] Dry mouth/salivary gland (xerostomia); [8] Fatigue (asthenia, lethargy, malaise); [9] Flushing; [10] Insomnia; [11] Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L); [12] Bilirubin (hyperbilirubinemia); [13] Infection with unknown ANC, vaginal; [14] Glucose, serum-high (hyperglycemia); [15] Alkaline phosphatase; [16] ALT, SGPT (serum glutamic pyruvic transaminase); [17] Calcium, serum-low (hypocalcemia); [18] Magnesium, serum-high (hypermagnesemia); [19] Potassium, serum-low (hypokalemia); [20] Sodium, serum-low (hyponatremia); [21] Mood alteration - Agitation; [22] Mood alteration - anxiety; [23] Productive cough; [24] Hiccoughs (hiccups, singultus); [25] Erythema to lips and leg patch; [26] Infection with unknown ANC - Skin - cellulitis; [27] Vaginal ulceration lesion

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. C. Belani
• Organization: MSHERSHEY MC
• Phone: 717-531-1078
• EMail: cbelani@psu.edu

• Responsible Party: Chandra P. Belani, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT00702962
• Other Study ID Numbers: PSHCI 08-005
• First Submitted: June 19, 2008
• First Posted: June 20, 2008
• Results First Submitted: July 24, 2017
• Results First Posted: October 15, 2018
• Last Update Posted: October 22, 2018