Trial Outcomes & Findings for Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma (NCT NCT01614795)

Last Updated: 2018-12-11

Results Overview

Per Response evaluation criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions: Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR)= CR+PR. The combination of sufficient activity is considered if the true response rate is 35% or greater.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

46 participants

Primary outcome timeframe

6 cycles (168 days)

Results posted on

2018-12-11

Participant Flow

The analysis strategy for secondary outcome measures accommodates the possibility that the Progression-Free Interval and IHC could have different statistical characteristics across the different histologies that define the study groups.

Participant milestones

Participant milestones
Measure	Group 1 Relapsed or Refractory Osteosarcoma Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 2 Relapsed or Refractory Ewing Sarcoma/Peripheral PNET Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 3 Relapsed or Refractory Rhabdomyosarcoma Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 4 Relapsed or Refractory Non-rhabdo Soft Tissue Sarcoma Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies
Overall Study STARTED	11	12	11	12
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	11	12	11	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Group 1 Relapsed or Refractory Osteosarcoma Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 2 Relapsed or Refractory Ewing Sarcoma/Peripheral PNET Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 3 Relapsed or Refractory Rhabdomyosarcoma Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 4 Relapsed or Refractory Non-rhabdo Soft Tissue Sarcoma Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies
Overall Study Adverse Event	0	0	1	1
Overall Study Lack of Efficacy	10	10	9	8
Overall Study Physician Decision	1	0	1	1
Overall Study Withdrawal by Subject	0	1	0	2
Overall Study Ineligible	0	1	0	0

Baseline Characteristics

Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group 1 Relapsed or Refractory Osteosarcoma n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 2 Relapsed or Refractory Ewing Sarcoma/Peripheral PNET n=12 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 3 Relapsed or Refractory Rhabdomyosarcoma n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 4 Relapsed or Refractory Non-rhabdo Soft Tissue Sarcoma n=12 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Total n=46 Participants Total of all reporting groups
Age, Categorical <=18 years	7 Participants n=5 Participants	8 Participants n=7 Participants	9 Participants n=5 Participants	7 Participants n=4 Participants	31 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	4 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants	15 Participants n=21 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Continuous	18 years n=5 Participants	17.5 years n=7 Participants	14 years n=5 Participants	17.5 years n=4 Participants	17 years n=21 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	6 Participants n=7 Participants	8 Participants n=5 Participants	5 Participants n=4 Participants	20 Participants n=21 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	6 Participants n=7 Participants	3 Participants n=5 Participants	7 Participants n=4 Participants	26 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	0 Participants n=4 Participants	4 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants n=5 Participants	12 Participants n=7 Participants	8 Participants n=5 Participants	11 Participants n=4 Participants	41 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants	4 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Race (NIH/OMB) White	7 Participants n=5 Participants	8 Participants n=7 Participants	9 Participants n=5 Participants	7 Participants n=4 Participants	31 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	6 Participants n=21 Participants
Region of Enrollment United States	11 participants n=5 Participants	11 participants n=7 Participants	11 participants n=5 Participants	12 participants n=4 Participants	45 participants n=21 Participants
Region of Enrollment Canada	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants

PRIMARY outcome

Timeframe: 6 cycles (168 days)

Population: One (1) of the patients in Group 1 and one (1) of the patients in Group 4 were considered inevaluable for response assessment. One (1) of the patients in Group 2 was ineligible.

Outcome measures

Outcome measures
Measure	Group 1 Relapsed or Refractory Osteosarcoma n=10 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 2 Relapsed or Refractory Ewing Sarcoma/Peripheral PNET n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 3 Relapsed or Refractory Rhabdomyosarcoma n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 4 Relapsed or Refractory Non-rhabdo Soft Tissue Sarcoma n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies
Objective Response Rate (PR or CR) by Response Evaluation Criteria in Solid Tumors (RECIST). Non-Responder	10 participants	11 participants	11 participants	11 participants
Objective Response Rate (PR or CR) by Response Evaluation Criteria in Solid Tumors (RECIST). Responder	0 participants	0 participants	0 participants	0 participants

PRIMARY outcome

Timeframe: Duration of protocol therapy - Up to 25 cycles (700 days)

Population: One hundred six (106) cycles were reported for the analysis of this toxicity

The number of patients-cycles where CTC Version 4 grade 3 or higher increased Alanine aminotransferase was observed

Outcome measures

Outcome measures
Measure	Group 1 Relapsed or Refractory Osteosarcoma n=106 cycles Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 2 Relapsed or Refractory Ewing Sarcoma/Peripheral PNET Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 3 Relapsed or Refractory Rhabdomyosarcoma Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 4 Relapsed or Refractory Non-rhabdo Soft Tissue Sarcoma Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies
Number of Cycles of Toxicity Alkaline phosphatase	1 cycles	—	—	—
Number of Cycles of Toxicity Anaphylaxis	1 cycles	—	—	—
Number of Cycles of Toxicity Anemia	3 cycles	—	—	—
Number of Cycles of Toxicity Ascites	1 cycles	—	—	—
Number of Cycles of Toxicity Aspartate aminotransferase	3 cycles	—	—	—
Number of Cycles of Toxicity Decreased lymphocyte count	1 cycles	—	—	—
Number of Cycles of Toxicity Decreased platelet count	5 cycles	—	—	—
Number of Cycles of Toxicity Decreased white blood cells	3 cycles	—	—	—
Number of Cycles of Toxicity Duodenal obstruction	1 cycles	—	—	—
Number of Cycles of Toxicity Epistaxis	1 cycles	—	—	—
Number of Cycles of Toxicity Extremity pain	1 cycles	—	—	—
Number of Cycles of Toxicity Hyperglycemia	1 cycles	—	—	—
Number of Cycles of Toxicity Hypermagnesemia	1 cycles	—	—	—
Number of Cycles of Toxicity Hypertriglyceridemia	2 cycles	—	—	—
Number of Cycles of Toxicity Hyperuricemia	1 cycles	—	—	—
Number of Cycles of Toxicity Hypoalbuminemia	1 cycles	—	—	—
Number of Cycles of Toxicity Hypokalemia	5 cycles	—	—	—
Number of Cycles of Toxicity Hyponatremia	1 cycles	—	—	—
Number of Cycles of Toxicity Hypophosphatemia	4 cycles	—	—	—
Number of Cycles of Toxicity Hypoxia	1 cycles	—	—	—
Number of Cycles of Toxicity Increased alanine aminotransferase	2 cycles	—	—	—
Number of Cycles of Toxicity Increased blood bilirubin	1 cycles	—	—	—
Number of Cycles of Toxicity Increased creatinine	1 cycles	—	—	—
Number of Cycles of Toxicity Multi-organ failure	1 cycles	—	—	—
Number of Cycles of Toxicity Neutopenia	6 cycles	—	—	—
Number of Cycles of Toxicity Non-cardiac chest pain	1 cycles	—	—	—
Number of Cycles of Toxicity Other cardiac disorders	1 cycles	—	—	—
Number of Cycles of Toxicity Other infections and infestations	1 cycles	—	—	—
Number of Cycles of Toxicity Oral mucocitis	4 cycles	—	—	—
Number of Cycles of Toxicity Pain	2 cycles	—	—	—
Number of Cycles of Toxicity Paronychia	1 cycles	—	—	—
Number of Cycles of Toxicity Urinary tract infection	1 cycles	—	—	—
Number of Cycles of Toxicity Urinary tract obstruction	1 cycles	—	—	—
Number of Cycles of Toxicity Weight loss	1 cycles	—	—	—
Number of Cycles of Toxicity Wound infection	1 cycles	—	—	—

SECONDARY outcome

Timeframe: 10 months after enrollment

Population: The 10 month time point was chosen since the shortest follow-up available was observed in Group 3 (relapsed or refractory rhabdomyosarcoma) where the last patient under observation was censored after completing 10 months of follow-up

Percentage Probability of remaining progression-free 5 years after enrollment estimated by the method of Kaplan and Meier

Outcome measures

Outcome measures
Measure	Group 1 Relapsed or Refractory Osteosarcoma n=10 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 2 Relapsed or Refractory Ewing Sarcoma/Peripheral PNET n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 3 Relapsed or Refractory Rhabdomyosarcoma n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 4 Relapsed or Refractory Non-rhabdo Soft Tissue Sarcoma n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies
Progression-free Interval	9.09 percent probability Interval 0.54 to 33.29	9.09 percent probability Interval 0.54 to 33.29	9.09 percent probability Interval 0.54 to 33.29	16.67 percent probability Interval 2.65 to 41.3

SECONDARY outcome

Timeframe: Baseline

Population: All specimens for the IHC analysis for IGF-1R, Insulin Receptor, ERK, RON, and mTOR were obtained prior to the start of treatment on ADVL1221. Levels 0, 1+, 2+ and 3+ represent increasing strengths of IHC staining.

Number of patients expressing insulin-like growth factor 1 receptor (IGF-1R), insulin receptor, ERK, RON, and mammalian target of rapamycin (mTOR) at levels 0, 1+, 2+, 3+ by immunohistochemistry.

Outcome measures

Outcome measures
Measure	Group 1 Relapsed or Refractory Osteosarcoma n=10 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 2 Relapsed or Refractory Ewing Sarcoma/Peripheral PNET n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 3 Relapsed or Refractory Rhabdomyosarcoma n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 4 Relapsed or Refractory Non-rhabdo Soft Tissue Sarcoma n=11 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR RON level 2+	0 Participants	0 Participants	0 Participants	0 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR RON level 3+	0 Participants	0 Participants	0 Participants	1 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR mTOR level 1+	2 Participants	3 Participants	1 Participants	3 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR mTOR level 2+	0 Participants	1 Participants	0 Participants	0 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR Insulin receptor level 3+	1 Participants	2 Participants	2 Participants	2 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR ERK level 0	2 Participants	5 Participants	6 Participants	3 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR ERK level 1+	5 Participants	5 Participants	2 Participants	4 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR ERK level 2+	1 Participants	0 Participants	3 Participants	3 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR ERK Level 3+	2 Participants	1 Participants	0 Participants	1 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR RON level 0	7 Participants	10 Participants	10 Participants	6 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR RON level 1+	3 Participants	1 Participants	1 Participants	4 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR mTOR level 0	8 Participants	7 Participants	10 Participants	8 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR mTOR level 3+	0 Participants	0 Participants	0 Participants	0 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR IGF-1R level 0	2 Participants	4 Participants	1 Participants	3 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR IGF-1R level 1+	4 Participants	3 Participants	0 Participants	4 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR IGF-1R level 2+	2 Participants	2 Participants	2 Participants	5 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR IGF-1R level 3+	2 Participants	2 Participants	8 Participants	1 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR Insulin receptor level 0	4 Participants	4 Participants	4 Participants	3 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR Insulin receptor level 1+	2 Participants	2 Participants	1 Participants	2 Participants
Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR Insulin receptor level 2+	2 Participants	3 Participants	4 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline

Population: 2 patients of the 12 patients enrolled in the Ewing Sarcoma stratum submitted specimens for analysis

Outcome measures

Outcome measures
Measure	Group 1 Relapsed or Refractory Osteosarcoma n=2 Participants Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 2 Relapsed or Refractory Ewing Sarcoma/Peripheral PNET Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 3 Relapsed or Refractory Rhabdomyosarcoma Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 4 Relapsed or Refractory Non-rhabdo Soft Tissue Sarcoma Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies
Number of Patients With Detectable Bone Marrow Micrometastatic Disease Estimated as the Proportion of Eligible Patients Entered Into the Ewing Sarcoma Stratum Who Have Detectable Tumor Cells in the Marrow at Enrollment	0 Participants	—	—	—

Adverse Events

Group 1 Relapsed or Refractory Osteosarcoma

Serious events: 2 serious events

Other events: 11 other events

Deaths: 0 deaths

Group 2 Relapsed or Refractory Ewing Sarcoma/Peripheral PNET

Serious events: 3 serious events

Other events: 5 other events

Deaths: 0 deaths

Group 3 Relapsed or Refractory Rhabdomyosarcoma

Serious events: 2 serious events

Other events: 7 other events

Deaths: 0 deaths

Group 4 Relapsed or Refractory Non-rhabdo Soft Tissue Sarcoma

Serious events: 7 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Results Reporting Coordinator

Children's Oncology Group

Phone: 626-447-0064

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Group 1 Relapsed or Refractory Osteosarcoma n=11 participants at risk Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 2 Relapsed or Refractory Ewing Sarcoma/Peripheral PNET n=11 participants at risk Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 3 Relapsed or Refractory Rhabdomyosarcoma n=11 participants at risk Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies	Group 4 Relapsed or Refractory Non-rhabdo Soft Tissue Sarcoma n=12 participants at risk Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. cixutumumab: Given IV, Days 1, 8, 15, and 22, dosage 6 mg/kg. Cixutumumab dose is based on weight (kg). temsirolimus: Given IV, Days 1, 8, 15, and 22 8 mg/m2 (maximum dose = 16 mg) (Cycle 1), Dose escalation to 10 mg/m2 (maximum dose = 20 mg). Temsirolimus dose is based on BSA. laboratory biomarker analysis: Correlative studies
Blood and lymphatic system disorders Anemia	18.2% 2/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	18.2% 2/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Psychiatric disorders Confusion	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	9.1% 1/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Investigations Creatinine increased	9.1% 1/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	8.3% 1/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	9.1% 1/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Metabolism and nutrition disorders Hyperglycemia	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	9.1% 1/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Vascular disorders Hypertension	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	8.3% 1/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Metabolism and nutrition disorders Hypokalemia	27.3% 3/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	8.3% 1/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Metabolism and nutrition disorders Hyponatremia	18.2% 2/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Metabolism and nutrition disorders Hypophosphatemia	18.2% 2/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	8.3% 1/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	8.3% 1/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Investigations Lymphocyte count decreased	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	9.1% 1/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Gastrointestinal disorders Mucositis oral	45.5% 5/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	9.1% 1/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	27.3% 3/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	25.0% 3/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Investigations Neutrophil count decreased	27.3% 3/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	9.1% 1/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	8.3% 1/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
General disorders Pain	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	8.3% 1/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Infections and infestations Paronychia	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	9.1% 1/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Investigations Platelet count decreased	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	18.2% 2/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	27.3% 3/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Nervous system disorders Tremor	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	9.1% 1/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Investigations White blood cell decreased	18.2% 2/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/11 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	8.3% 1/12 SAE field contains NCI Common Toxicity Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.