Advanced Cancer
Conditions
Keywords
Advanced solid tumors including MPM and NSCLC
Brief summary
The purpose of this investigational study is to determine the safety and tolerability of oral suberoylanilide hydroxamic acid when administered in combination with standard doses of pemetrexed and cisplatin for the treatment of advanced solid tumors.
Interventions
DRUGvorinostat (Suberoylanilide Hydroxamic Acid [SAHA]) in combination with Pemetrexed and Cisplatin
Dose escalation study starting with vorinostat (Suberoylanilide Hydroxamic Acid \[SAHA\]) capsules 200 mg b.i.d. in combination with Pemetrexed and Cisplatin (see table for Reporting Groups).
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient must be 18 years or older with confirmed diagnosis of a solid tumor for which pemetrexed and cisplatin is acceptable treatment and have received no more than 2 prior systemic therapies * Has at least 1 measurable lesion * Has adequate blood, liver, and kidney functions * Has not received any chemotherapy for at least 4 weeks prior to entry in this study * Agrees to take adequate measures to prevent pregnancy as outlined in the protocol
Exclusion criteria
* Patient has been treated with other investigational agents with a similar anti-tumor mechanism * Patient from Cohorts A and B has received pemetrexed or cisplatin within the past 6 months and from Cohorts C and D have received pemetrexed within the past 6 months * Patient from Cohorts A and B has preexisting Grade 2 or higher neuropathy and from Cohorts C and D have Grade 3 or higher neuropathy * Patient has active infection or had received IV (intravenous) antibiotic, antiviral, or antifungal medications within 2 weeks of the start of study drugs * Patient has HIV, hepatitis B or hepatitis C infection * Patient is pregnant or breast feeding * Patient has allergy to any component of the study drugs * Patient has history of GI (gastrointestinal) surgery or conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | Cycle 1 (21 days) | MTD was determined by the occurrence of DLTs during the first treatment cycle. DLT describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. The dose level is equal to the MTD if \< 2 patients experience a DLT and is also the highest tolerated dose level in the cohort. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability as Measured by the Number of Participants With Disease Progression | Any time during 8 cycle treatment period through 30 days after. | Number of participants with disease progression (protocol-mandated reason for discontinuation). Disease progression was determined by the principle investigator. |
Participant flow
Recruitment details
First Patient In = 29-Aug-05. Last Patient Last Visit = 03-Dec-07. Multicenter (4 Outpatient Clinics) in US.
Pre-assignment details
Post-group assignment information: For all cohorts doses were administered in repeated 21-day cycles. Determination of the Maximum Tolerated Dose (MTD), by using dose-escalating design and measured by Dose Limiting Toxicity (DLT) is a standard procedure in the development of chemotherapeutic combinations.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A - Vorinostat BID + Pemetrexed + Cisplatin Dose level A.1 - Vorinostat 200 mg twice daily (BID) for 14 days out of 3 weeks + Pemetrexed + Cisplatin
Dose level A.2 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first week, two weeks off + Pemetrexed + Cisplatin | 13 |
| Cohort B - Vorinostat QD + Pemetrexed + Cisplatin Dose level B.1 - Vorinostat 300 mg once daily (QD) for 7 days + Pemetrexed + Cisplatin
Dose level B.2 - Vorinostat 400 mg once daily (QD) for 7 days + Pemetrexed + Cisplatin | 9 |
| Cohort C - Vorinostat BID + Pemetrexed Dose level C.1 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first week, two weeks off + Pemetrexed
Dose level C.2 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first two weeks, one week off + Pemetrexed
Dose level C.3 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days repeated weekly + Pemetrexed | 14 |
| Cohort D - Vorinostat QD + Pemetrexed Dose level D.1 - Vorinostat 300 mg once daily (QD) for 7 days + Pemetrexed
Dose level D.2 - Vorinostat 400 mg once daily (QD) for 7 days + Pemetrexed | 16 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | > 14 day delay in therapy start | 0 | 1 | 0 | 0 |
| Overall Study | Adverse Event | 5 | 4 | 3 | 3 |
| Overall Study | Progressive Disease | 4 | 1 | 9 | 10 |
| Overall Study | Received radiation on new therapy | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort A - Vorinostat BID + Pemetrexed + Cisplatin | Cohort B - Vorinostat QD + Pemetrexed + Cisplatin | Cohort C - Vorinostat BID + Pemetrexed | Cohort D - Vorinostat QD + Pemetrexed | Total |
|---|---|---|---|---|---|
| Age Continuous | 60.52 years | 58.23 years | 60.09 years | 63.63 years | 61 years |
| Race/Ethnicity Asian | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity Black | 0 participants | 2 participants | 0 participants | 1 participants | 3 participants |
| Race/Ethnicity European | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity Hispanic American | 1 participants | 0 participants | 0 participants | 2 participants | 3 participants |
| Race/Ethnicity White | 12 participants | 6 participants | 14 participants | 12 participants | 44 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 7 Participants | 8 Participants | 24 Participants |
| Sex: Female, Male Male | 9 Participants | 4 Participants | 7 Participants | 8 Participants | 28 Participants |
Outcome results
Primary
Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level
MTD was determined by the occurrence of DLTs during the first treatment cycle. DLT describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. The dose level is equal to the MTD if \< 2 patients experience a DLT and is also the highest tolerated dose level in the cohort.
Time frame: Cycle 1 (21 days)
Population: A total of 52 participants were enrolled in this study. Six were violations pts (1 in Cohort C Dose Level 1, 1 in Cohort C Dose Level 2, 3 in Cohort D Dose Level 1, and 1 in Cohort D Dose Level 2) and were replaced. None of the violations pts had any DLTs in the first cycle of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Level A.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | Number (#) of DLT | 1 Participants |
| Dose Level A.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level <MTD | 0 Participants |
| Dose Level A.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level =MTD | 6 Participants |
| Dose Level A.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level >MTD | 0 Participants |
| Dose Level A.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level >MTD | 7 Participants |
| Dose Level A.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | Number (#) of DLT | 3 Participants |
| Dose Level A.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level <MTD | 0 Participants |
| Dose Level A.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level =MTD | 0 Participants |
| Dose Level B.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level <MTD | 0 Participants |
| Dose Level B.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level >MTD | 0 Participants |
| Dose Level B.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level =MTD | 3 Participants |
| Dose Level B.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | Number (#) of DLT | 0 Participants |
| Dose Level B.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | Number (#) of DLT | 2 Participants |
| Dose Level B.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level <MTD | 0 Participants |
| Dose Level B.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level =MTD | 0 Participants |
| Dose Level B.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level >MTD | 6 Participants |
| Dose Level C.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level =MTD | 0 Participants |
| Dose Level C.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level <MTD | 7 Participants |
| Dose Level C.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | Number (#) of DLT | 1 Participants |
| Dose Level C.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level >MTD | 0 Participants |
| Dose Level C.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level >MTD | 0 Participants |
| Dose Level C.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | Number (#) of DLT | 0 Participants |
| Dose Level C.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level =MTD | 0 Participants |
| Dose Level C.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level <MTD | 4 Participants |
| Dose Level C.3 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level =MTD | 3 Participants |
| Dose Level C.3 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level <MTD | 0 Participants |
| Dose Level C.3 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level >MTD | 0 Participants |
| Dose Level C.3 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | Number (#) of DLT | 0 Participants |
| Dose Level D.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level <MTD | 0 Participants |
| Dose Level D.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level >MTD | 0 Participants |
| Dose Level D.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level =MTD | 9 Participants |
| Dose Level D.1 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | Number (#) of DLT | 1 Participants |
| Dose Level D.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | Number (#) of DLT | 2 Participants |
| Dose Level D.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level >MTD | 7 Participants |
| Dose Level D.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level =MTD | 0 Participants |
| Dose Level D.2 | Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level | # Participants treated at a dose level <MTD | 0 Participants |
Secondary
Safety and Tolerability as Measured by the Number of Participants With Disease Progression
Number of participants with disease progression (protocol-mandated reason for discontinuation). Disease progression was determined by the principle investigator.
Time frame: Any time during 8 cycle treatment period through 30 days after.
Population: All participants. Treated Population includes all participants who received at least one dose and had efficacy measurements at baseline and at least one post baseline treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level A.1 | Safety and Tolerability as Measured by the Number of Participants With Disease Progression | 4 Participants |
| Dose Level A.2 | Safety and Tolerability as Measured by the Number of Participants With Disease Progression | 1 Participants |
| Dose Level B.1 | Safety and Tolerability as Measured by the Number of Participants With Disease Progression | 9 Participants |
| Dose Level B.2 | Safety and Tolerability as Measured by the Number of Participants With Disease Progression | 10 Participants |