Trial Outcomes & Findings for RAD001 in Combination With Cetuximab and Cisplatin in Recurrent and Metastatic SCCHN (NCT NCT01009346)

Last Updated: 2018-07-17

Results Overview

MTD will be defined as a) the dose of RAD001 producing DLT in 0-1 out of 6 patients, or b) the dose level below the dose which produced DLT in \<2 out of 6 patients, or c) the dose of 10mg po qd with less than 33% rate of DLT

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

9 participants

Primary outcome timeframe

6 months

Results posted on

2018-07-17

Participant Flow

Early Termination.

Early Termination

Participant milestones

Participant milestones
Measure	RAD001 Daily RAD001 in combination with weekly cetuximab and cisplatin/ carboplatin on Day 1, 8 of each 28 day cycle.
Overall Study STARTED	9
Overall Study COMPLETED	5
Overall Study NOT COMPLETED	4

Reasons for withdrawal

Reasons for withdrawal
Measure	RAD001 Daily RAD001 in combination with weekly cetuximab and cisplatin/ carboplatin on Day 1, 8 of each 28 day cycle.
Overall Study Adverse Event	4

Baseline Characteristics

RAD001 in Combination With Cetuximab and Cisplatin in Recurrent and Metastatic SCCHN

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Study Arm n=9 Participants Drug: RAD001 Other Names: Everolimus Dose Level -1 2.5mg/day Dose Level 1 5mg/day\* Dose Level 2 10mg/day MTD RAD001 Drug: Cetuximab Other Names: Erbitux 250mg/m2/week Drug: Cisplatin Other Names: cisplatinum CDDP cis-diamminedichloroplatinum(II) 40mg/m2 Day 1, 8 every 28 days Drug: Carboplatin Other Names: cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II) Carboplatin will be administered on Day1 and Day 8 of each 28 day cycle to a target AUC of 3 over 30 minutes. Carboplatin will be dosed using the Calvert formula: Total dose (mg) = (target AUC) x (glomerular filtration rate + 25) Creatinine clearance will be used to estimate the GFR. The Cockgroft-Gault formula will be used to estimate the creatinine clearance.
Age, Continuous	65.77778 years STANDARD_DEVIATION 12.71591 • n=5 Participants
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=5 Participants
Age, Categorical >=65 years	6 Participants n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants
Region of Enrollment United States	9 participants n=5 Participants

PRIMARY outcome

Timeframe: 6 months

Population: Patients who received at least one cycle of RAD001 were included in the analysis.

Outcome measures

Outcome measures
Measure	Study Arm (RAD001, Cetuximab, Cisplatin or Carboplatin) n=7 Participants Phase I will be a single arm , dose finding study to determine the maximum tolerated dose (MTD) of daily RAD001 in combination with weekly cetuximab and cisplatin on Day 1, 8 of each 28 day cycle. The combination will be explored in successive cohorts of 3 patients each. The first cohort of 3 patients will receive doses corresponding to the first dose level. A full safety evaluation will be conducted when these patients have completed 8 weeks of therapy (2 cycles). If 0/3 patients treated at a dose level have a DLT, then a new cohort of 3 patients will receive treatment at the next dose level. If 1/3 patients have even one DLT, then 3 more patients will be treated at same dose level. If none of these patients has a DLT, then the next higher dose level will be administered to the next cohort of 3 patients; otherwise the inferior dose level will be considered the MTD. If \>2/3 patients have a DLT, then the inferior dose level will be considered the MTD.
Maximum Tolerated Dose (MTD) of RAD001 in Combination With Cetuximab and Cisplatin.	10 mg

SECONDARY outcome

Timeframe: 2 years

Population: Only 5 patients received at least one cycle of RAD001

Median number of months for which participants are free of progression after initiating treatment with RAD001 in combination with weekly cetuximab and cisplatin.

Outcome measures

Outcome measures
Measure	Study Arm (RAD001, Cetuximab, Cisplatin or Carboplatin) n=5 Participants Phase I will be a single arm , dose finding study to determine the maximum tolerated dose (MTD) of daily RAD001 in combination with weekly cetuximab and cisplatin on Day 1, 8 of each 28 day cycle. The combination will be explored in successive cohorts of 3 patients each. The first cohort of 3 patients will receive doses corresponding to the first dose level. A full safety evaluation will be conducted when these patients have completed 8 weeks of therapy (2 cycles). If 0/3 patients treated at a dose level have a DLT, then a new cohort of 3 patients will receive treatment at the next dose level. If 1/3 patients have even one DLT, then 3 more patients will be treated at same dose level. If none of these patients has a DLT, then the next higher dose level will be administered to the next cohort of 3 patients; otherwise the inferior dose level will be considered the MTD. If \>2/3 patients have a DLT, then the inferior dose level will be considered the MTD.
Progression Free Survival (PFS) of RAD001 in Combination With Weekly Cetuximab and Cisplatin.	2.8 months Interval 1.6 to 13.9

Adverse Events

RAD001/Cetuximab/Cisplatin or Carboplatin

Serious events: 8 serious events

Other events: 2 other events

Deaths: 9 deaths

Serious adverse events

Serious adverse events
Measure	RAD001/Cetuximab/Cisplatin or Carboplatin n=9 participants at risk This was a dose escalation study with RAD001 in combination with cetuximab and cisplatin in recurrent/metastatic SCCHN. Patients with ECOG performance status 0-2, with no prior systemic therapy for recurrent/metastatic SCCHN were enrolled. The dose levels for RAD001 were 2.5mg, 5mg or 10 mg administered oral daily, cetuximab 250mg/m2 weekly infusion, and cisplatin 40mg/m2 days 1 and 8. Each cycle was 28 days. Safety monitoring plan was outlined in the protocol and study calendar at specific time points. Response was evaluated with CT/MRI and PET scans every 2 cycles. DLT criteria and MTD was defined.
Gastrointestinal disorders GERD	11.1% 1/9 • Number of events 1 • 3 years. Early termination due to toxicity with the RAD001 in combination with cetuximab and cisplatin.
General disorders Infusion Reaction (Cetuximab)	11.1% 1/9 • Number of events 1 • 3 years. Early termination due to toxicity with the RAD001 in combination with cetuximab and cisplatin.
Renal and urinary disorders Acute Renal Failure	11.1% 1/9 • Number of events 1 • 3 years. Early termination due to toxicity with the RAD001 in combination with cetuximab and cisplatin.
Respiratory, thoracic and mediastinal disorders Pleural Effusion	11.1% 1/9 • Number of events 1 • 3 years. Early termination due to toxicity with the RAD001 in combination with cetuximab and cisplatin.
Respiratory, thoracic and mediastinal disorders Mucosal Edema (Laryngeal and Hypopharyngeal)	11.1% 1/9 • Number of events 1 • 3 years. Early termination due to toxicity with the RAD001 in combination with cetuximab and cisplatin.
General disorders Aspiration	11.1% 1/9 • Number of events 1 • 3 years. Early termination due to toxicity with the RAD001 in combination with cetuximab and cisplatin.
Respiratory, thoracic and mediastinal disorders Airway Edema	11.1% 1/9 • Number of events 1 • 3 years. Early termination due to toxicity with the RAD001 in combination with cetuximab and cisplatin.
General disorders Septic Shock	11.1% 1/9 • Number of events 1 • 3 years. Early termination due to toxicity with the RAD001 in combination with cetuximab and cisplatin.

Other adverse events

Other adverse events
Measure	RAD001/Cetuximab/Cisplatin or Carboplatin n=9 participants at risk This was a dose escalation study with RAD001 in combination with cetuximab and cisplatin in recurrent/metastatic SCCHN. Patients with ECOG performance status 0-2, with no prior systemic therapy for recurrent/metastatic SCCHN were enrolled. The dose levels for RAD001 were 2.5mg, 5mg or 10 mg administered oral daily, cetuximab 250mg/m2 weekly infusion, and cisplatin 40mg/m2 days 1 and 8. Each cycle was 28 days. Safety monitoring plan was outlined in the protocol and study calendar at specific time points. Response was evaluated with CT/MRI and PET scans every 2 cycles. DLT criteria and MTD was defined.
Metabolism and nutrition disorders Hypophosphatemia	22.2% 2/9 • Number of events 2 • 3 years. Early termination due to toxicity with the RAD001 in combination with cetuximab and cisplatin.

Additional Information

Ranee Mehra, MD

Johns Hopkins

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60