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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00702962
Recruitment Status : Terminated (Poor accrual)
First Posted : June 20, 2008
Results First Posted : October 15, 2018
Last Update Posted : October 22, 2018
Sponsor:
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
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
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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
Arm/Group Title PHASE I: Vorinostat 200mg Carbo 6 (AUC) PHASE II: Vorinostat 300mg Carbo 6 (AUC) Total
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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
Hide 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%
1.Primary Outcome
Title Assess Maximum Tolerated Dose of Vorinostat When Combined With Carboplatin and Etoposide of Patients With Extensive Disease SCLC
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
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)
Hide 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%)    
Hide 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
Hide 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
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
Layout table for Results Point of Contact information
Name/Title: Dr. C. Belani
Organization: MSHERSHEY MC
Phone: 717-531-1078
EMail: cbelani@psu.edu
Layout table for additonal information
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