A Study of Olaratumab Alone and in Combination With Standard Chemotherapies in Children With Cancer

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to evaluate the safety of different doses of olaratumab and to determine which dose should be used for future pediatric studies. The present study is open to children with advanced cancer or cancer that has spread to another part of the body. The study has three parts. In the first two parts, a specific dose of olaratumab will be given in 21 day cycles, followed by one of three standard chemotherapy regimens. In the third part, a specific dose of olaratumab will be given with one of three standard chemotherapy regimens in 21 day cycles. Participants will only enroll in one part.

Official Title
-----------------
A Phase 1, Open-Label, Dose-Escalation Study of Olaratumab as a Single Agent and in Combination With Doxorubicin, Vincristine/Irinotecan, or High-Dose Ifosfamide in Pediatric Patients With Relapsed or Refractory Solid Tumors

Conditions
-----------------
Neoplasm Metastasis

Intervention / Treatment
-----------------
* Drug: Olaratumab
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Irinotecan
* Drug: Ifosfamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The participant must have histological or cytological evidence of a diagnosis of solid tumor, excluding lymphomas and melanoma, but including central nervous system (CNS) tumors, that is relapsed or refractory, not be amenable to curative treatment. The participant has the presence of measurable and/or nonmeasurable but evaluable disease as defined by the Response Evaluation Criteria In Solid Tumors (RECIST Version 1.1). Response Assessment in Neuro-Oncology (RANO) Criteria or Macdonald Criteria should be used for CNS tumors. The participant has a Lansky (<16 years of age) or Karnofsky (≥16 years of age) performance score of at least 50. The participant has adequate hematologic, organ, and coagulation function ≤2 weeks (14 days) prior to first dose of study drug: Absolute neutrophil count (ANC) ≥750 cubic millimeters (mm³) Platelets ≥75,000/mm³ Hemoglobin ≥8 grams per deciliter (g/dL) Total bilirubin (sum of conjugated + unconjugated) ≤1.5 x upper limit of normal (ULN) for age Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN Serum creatinine is based on age/gender Adequate coagulation function as defined by International Normalized Ratio ≤1.5 or prothrombin time ≤1.5 x ULN, and partial thromboplastin time ≤1.5 x ULN Both female and male participants of child-bearing potential must agree to use highly effective contraceptive precautions during the trial and up to 3 months following the last dose of olaratumab, or longer for other study drugs according to their label. Participants must have fully recovered from the acute toxic effects of all prior anticancer therapies or must adhere to post-treatment conditions as follows: Myelosuppressive chemotherapy Hematopoietic growth factors Biologic (anti-neoplastic agent) Antibody therapy Radiation Stem cell infusion without traumatic brain injury Corticosteroids Exclusion Criteria: Have received treatment within 21 days of the initial dose of olaratumab with an investigational product or non-approved use of a drug or device or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Participants that have had bone marrow or solid organ transplant are excluded. The participant has an active fungal, bacterial, and/or known severe viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required). Female participants who are pregnant or breastfeeding are excluded. If the participant is to be enrolled in the doxorubicin combination arm, a left ventricular dysfunction (LVEF < 50%) or shortening fraction of <27% by echocardiogram (either multigated acquisition [MUGA] or echocardiogram [ECHO] are required, not both). Participants that have received prior anthracycline therapy if the participant is to be enrolled in the doxorubicin combination arm.

Ages Eligible for Study
-----------------
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olaratumab + Doxorubicin (Part A)<br>Cycle 1: Olaratumab 15 mg/kg was administered IV Days 1 and 8. Cycle 2 and beyond: Olaratumab 15 mg/kg administered IV on Days 1 and 8 and doxorubicin administered IV on Days 1 and 2. Treatment will cease when discontinuation criterion is met. All cycles are 21 days. | Drug: Olaratumab<br>* Olaratumab administered IV.<br>* Other names: LY3012207;Drug: Doxorubicin<br>* Doxorubicin administered IV.<br>|
| Experimental: Olaratumab + Vincristine + Irinotecan (Part A)<br>Cycle 1: Olaratumab 15 mg/kg was administered IV Days 1 and 8. Cycle 2 and beyond: Olaratumab 15 mg/kg and vincristine administered IV on Days 1 and 8. Irinotecan administered IV on Days 1 through 5. Treatment will cease when discontinuation criterion is met. All cycles are 21 days. | Drug: Olaratumab<br>* Olaratumab administered IV.<br>* Other names: LY3012207;Drug: Vincristine<br>* Vincristine administered IV.<br>Drug: Irinotecan<br>* Irinotecan administered IV.<br>|
| Experimental: Olaratumab + Ifosfamide (Part A)<br>Cycle 1: Olaratumab 15 mg/kg was administered IV Days 1 and 8. Cycle 2 and beyond: Olaratumab 15 mg/kg administered IV on Days 1 and 8 of each cycle. Ifosfamide administered IV on Days 1 through 5. Treatment will cease when discontinuation criterion is met. All cycles are 21 days. | Drug: Olaratumab<br>* Olaratumab administered IV.<br>* Other names: LY3012207;Drug: Ifosfamide<br>* Ifosfamide administered IV.<br>|
| Experimental: Olaratumab + Doxorubicin (Part B)<br>Cycle 1: Olaratumab 20 mg/kg was administered IV Days 1 and 8. Cycle 2 and beyond: Olaratumab 20 mg/kg administered IV on Days 1 and 8 and doxorubicin administered IV on Days 1 and 2. Treatment will cease when discontinuation criterion is met. All cycles are 21 days. | Drug: Olaratumab<br>* Olaratumab administered IV.<br>* Other names: LY3012207;Drug: Doxorubicin<br>* Doxorubicin administered IV.<br>|
| Experimental: Olaratumab + Vincristine + Irinotecan (Part B)<br>Cycle 1: Olaratumab 20 mg/kg was administered IV Days 1 and 8. Cycle 2 and beyond: Olaratumab 20 mg/kg and vincristine administered IV on Days 1 and 8. Irinotecan administered IV on Days 1 through 5. Treatment will cease when discontinuation criterion is met. All cycles are 21 days. | Drug: Olaratumab<br>* Olaratumab administered IV.<br>* Other names: LY3012207;Drug: Vincristine<br>* Vincristine administered IV.<br>Drug: Irinotecan<br>* Irinotecan administered IV.<br>|
| Experimental: Olaratumab + Ifosfamide (Part B)<br>Cycle 1: Olaratumab 20 mg/kg was administered IV Days 1 and 8. Cycle 2 and beyond: Olaratumab 20 mg/kg administered IV on Days 1 and 8 of each cycle. Ifosfamide administered IV on Days 1 through 5. Treatment will cease when discontinuation criterion is met. All cycles are 21 days. | Drug: Olaratumab<br>* Olaratumab administered IV.<br>* Other names: LY3012207;Drug: Doxorubicin<br>* Doxorubicin administered IV.<br>Drug: Ifosfamide<br>* Ifosfamide administered IV.<br>|
| Experimental: Olaratumab + Doxorubicin (Part C)<br>Cycle 1 and beyond: Olaratumab 20 mg/kg administered IV on Days 1 and 8 and doxorubicin administered IV on Days 1 and 2. Treatment will cease when discontinuation criterion is met. All cycles are 21 days. | Drug: Olaratumab<br>* Olaratumab administered IV.<br>* Other names: LY3012207;Drug: Doxorubicin<br>* Doxorubicin administered IV.<br>|
| Experimental: Olaratumab + Vincristine + Irinotecan (Part C)<br>Cycle 1 and beyond: Olaratumab 20 mg/kg and vincristine administered IV on Days 1 and 8. Irinotecan administered IV on Days 1 through 5. Treatment will cease when discontinuation criterion is met. All cycles are 21 days. | Drug: Olaratumab<br>* Olaratumab administered IV.<br>* Other names: LY3012207;Drug: Vincristine<br>* Vincristine administered IV.<br>Drug: Irinotecan<br>* Irinotecan administered IV.<br>|
| Experimental: Olaratumab + Ifosfamide (Part C)<br>Cycle 1 and beyond: Olaratumab 20 mg/kg administered IV on Days 1 and 8 of each cycle. Ifosfamide administered IV on Days 1 through 5. Treatment will cease when discontinuation criterion is met. All cycles are 21 days. | Drug: Olaratumab<br>* Olaratumab administered IV.<br>* Other names: LY3012207;Drug: Ifosfamide<br>* Ifosfamide administered IV.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Olaratumab Dose Limiting Toxicities (DLTs) | A dose limiting toxicity (DLT) was defined as an adverse event (AE) during the first 21 days that was possibly related to the study drug and fulfilled any of the following criteria using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0: CTCAE Grade 3 nonhematologic toxicity, grade 4 neutropenia that lasted longer than 2 weeks, grade ≥3 thrombocytopenia complicated by hemorrhage, and any hematologic toxicity that caused a cycle delay of >14 days. | Parts A and B: Cycle 1 through Cycle 2 in each arm (21-day cycle); Part C: Cycle 1 only (21-day cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab Part A | Pharmacokinetics (PK): Maximum serum concentration (Cmax) data of Olaratumab was reported from available sample data. | Cycle 1, Day 8 and Cycle 2, Days 1 and 8: 1.25 hour (h), 2.5 h, 3.5h Postdose | 
| PK: Maximum Concentration (Cmax) of Olaratumab Part B | PK: Maximum serum concentration (Cmax) data of Olaratumab was reported from available sample data. | Cycle 1, Day 8 and Cycle 2, Days 1 and 8: 1.25 hour (h), 2.5 h, 3.5h Postdose | 
| PK: Maximum Concentration (Cmax) of Olaratumab Part C | Pharmacokinetics (PK): Maximum serum concentration (Cmax) data of Olaratumab was reported from available sample data. | Cycle 1, Days 1 and 8; Cycle 2, Days 1 and 8: 1.25 hour (h), 2.5 h, 3.5h Postdose | 
| PK: Trough Serum Minimum Concentration (Cmin) of Olaratumab Part A | PK: Trough serum concentration (Cmin) of Olaratumab was reported. A sample was collected every other cycle from cycles 1, 2, 3-25. | Cycles 1, 2, 3-25; Day 8: 336 Hours Postdose | 
| PK: Trough Serum Minimum Concentration (Cmin) of Olaratumab Part B | PK: Trough serum concentration (Cmin) of Olaratumab was reported. A sample was collected every other cycle from cycles 1, 2, 3-25. | Cycles 1, 2, 3-25; Day 8: 336 Hours Postdose | 
| PK: Trough Serum Minimum Concentration (Cmin) of Olaratumab Part C | PK: Trough serum concentration (Cmin) of Olaratumab was reported. A sample was collected every other cycle from cycles 1, 2, 3-25. | Cycles 1, 2, 3-25; Day 8: 336 Hours Postdose | 
| Percentage of Participants With a Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | Objective Response Rate (ORR) is the percentage of participants achieving a confirmed best overall tumor response of CR or PR. According to RECIST v1.1, PR defined as a >30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD; CR was defined as the disappearance of all target and non-target lesions. | Baseline to objective progression or start of new anti-cancer therapy (Up to 7 months) | 
| Progression Free Survival (PFS) | Progression-free survival (PFS) is defined as the time from baseline to the first date of radiological disease progression or death due to any cause. Progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). The appearance of one or more new lesions is also considered progression. If participant started new treatment before PD, the participant was censored at the date of last tumor assessment prior to new therapy. If treatment was discontinued for reasons other than PD and no further assessment, censoring occurred at last tumor assessment. | Baseline to radiological disease progression or death from any cause (Up to 2 Years) | 
| Percentage of Participants With Treatment Emergent (TE) Positive Anti-Olaratumab Antibodies | Percentage of participants with a TE positive anti-olaratumab antibodies defined as a participant with a 4-fold (2 dilutions) increase over a positive baseline antibody titer. | From Baseline to Study Completion (Up to 33 Months) |