Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Recurrence

Central Nervous System Neoplasms

Disease Attributes

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Bevacizumab

Everolimus

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

* Dose Level 0, Bevacizumab IV every 2 weeks 8 mg/kg, Everolimus 4 mg/m\^2
* Dose Level 1 (starting dose), Bevacizumab IV every 2 weeks 10 mg/kg, Everolimus 4 mg/m\^2
* Dose Level 2, Bevacizumab IV every 2 weeks 10 mg/kg, Everolimus 5 mg/m\^2

* Bevacizumab IV every 2 weeks
* Dose Level 0- 8 mg/kg
* Dose Level 1 (starting dose)- 10 mg/kg
* Dose Level 2- 10 mg/kg

* Everolimus
* Dose Level 0- 4 mg/m2
* Dose level 1 (starting dose)- 4 mg/m2
* Dose Level 2- 5 mg/m2

Victor Santana, MD

The main goals of this Phase I study are to learn about the side effects that may occur when everolimus and bevacizumab are given to children and young adults and to find the highest doses of these drugs that can be given together without causing severe side effects. Bevacizumab will be given into the vein (IV) over 30-90 minutes every two weeks and everolimus tablets will be given daily by mouth. A cycle of therapy will be four weeks.

This is a traditional phase I dose finding study to estimate the maximum tolerated dose (MTD) and describe the dose limiting toxicities (DLT) of the combination of bevacizumab, administered every 2 weeks IV and everolimus administered orally daily to children with recurrent or refractory solid tumors including CNS malignancies. Patients will receive bevacizumab every two weeks IV, and everolimus orally daily. Four consecutive weeks will constitute one course and subsequent courses will immediately follow with no break in the administration of either drug. In the absence of disease progression or unacceptable toxicity, treatment can continue for 2 years. The bevacizumab dose will start at 10 mg/kg. Everolimus will start at 4 mg/m2, 80% of the MTD established in our current phase I trial. A traditional 3+3 dose escalation/de-escalation design will be used to determine the joint MTD for these two agents. Doses to be studied are detailed in the table below. Consistent with the traditional design, we will enroll cohorts of 3 patients at each dose level starting with dose level 1 and will escalate to the next higher dose, if none of these 3 experiences a DLT. If one of 3 patients experiences a DLT at a dose level then 3 more patients will be studied at this level. If none of these 3 experiences a DLT then escalation to the next level will occur. Otherwise the current dose will be considered too toxic and de-escalation will occur. Under this setting, MTD will be the dose level at which 0/3 or 1/6 patient would have experienced DLT and the next dose level is determined to be too toxic.

Exploratory objectives:

1. To preliminarily define the antitumor activity of the combination of everolimus and bevacizumab within the confines of a phase I study
2. To assess the incidence of PTEN and PI3Kinase pathway activation in recurrent or refractory solid tumors of childhood
3. To assess everolimus pharmacokinetics in children, including the effect of concomitant drug therapy (e.g., dexamethasone).
4. To explore changes in correlative magnetic resonance imaging in children receiving everolimus and bevacizumab
5. To identify additional genes both within and outside of the mTOR pathway that may act as determinants of response to everolimus
6. To explore the pharmacogenetic polymorphisms responsible for everolimus disposition (e.g., metabolism and elimination)
7. To test the ability of everolimus to inhibit mTOR pathway signaling in patients with recurrent solid tumors including CNS malignancies in peripheral blood mononuclear cells
8. To estimate blood levels of VEGF, BFGF, TSP-1, I-CAM, v-CAM and circulating endothelial cells prior to, during therapy and after therapy

A Trial of Everolimus and Bevacizumab in Children With Recurrent Solid Tumors

A Phase I Trial of RAD001 (Everolimus) and Avastin(R) (Bevacizumab) in Children With Recurrent Solid Tumors

Novartis Pharmaceuticals

St. Jude Children's Research Hospital

Nervous System Neoplasms

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Endothelial Growth Factors

Mitogens

Ramucirumab

(Part A-Non-CNS Solid Tumors) Escalating doses of 8 milligrams per kilogram (mg/kg) or 12 mg/kg Ramucirumab administered as an intravenous infusion every 2 weeks (Q2W) with 3 doses per 42 day cycle.

(Part B-CNS Tumors) Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

The main purpose of this study is to evaluate the safety of the study drug known as ramucirumab in children with recurrent or refractory solid tumors including central nervous system (CNS) tumors.

A Study of Ramucirumab (LY3009806) in Children With Refractory Solid Tumors

A Phase 1 Study Of Ramucirumab, a Human Monoclonal Antibody Against the Vascular Endothelial Growth Factor-2 (VEGFR-2) Receptor in Children With Refractory Solid Tumors, Including CNS Tumors

A DLT is defined as an Adverse Event (AE) that is likely related to the study medication or combination, and fulfills any one of the following criteria, graded according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0:

1. Any death not clearly due to the underlying disease or extraneous causes 2. Neutropenic fever 2. Any Grade ≥3 non-hematologic toxicity 3. Grade ≥4 neutropenia or thrombocytopenia \>7 days 4. Grade ≥3 thrombocytopenia with bleeding 5. Grade ≥3 nausea/vomiting or diarrhea\>72 hours with adequate antiemetic and other supportive care 6. Grade ≥3 fatigue ≥1 week 7. Grade ≥3 electrolyte abnormality that lasts\>72 hours, unless the Participant has clinical symptoms, in which case all Grade 3+electrolyte abnormality regardless of duration should count as a DLT.

8. Grade ≥3 prolongation of QT interval corrected using the Fridericia formula on 2 separate electrocardiogram readings approximately 5 min apart.

Population Pharmacokinetics (PK): Minimum observed plasma concentration of Ramucirumab.

Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline.

Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants per cohort with at least 1 measurable lesion, multiplied by 100. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

DOR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

Overall survival is defined as the time from date of randomization to the date of death (due to any cause). For participants whose last known status is alive at the data cutoff date for the analysis, time will be censored as the last contact date prior to the data cutoff date.

Children's Oncology Group

Eli Lilly and Company

All randomized participants who received at least one dose of study drug.

Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion Q2W with 3 doses per 42 day cycle.

8 mg/kg Ramucirumab (Part A)

Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.

12 mg/kg Ramucirumab (Part A)

12 mg/kg Ramucirumab (Part B)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Chief Medical Officer

All randomized participants from Part A, who received at least one dose of study drug.

Part A: Number of Participants With Dose Limiting Toxicities (DLTs): Maximum Tolerated Dose of Ramucirumab

Cycle 1 Day 1

Cycle 1 Day 43

Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion every 2 weeks (Q2W) with 3 doses per 42 day cycle.

8 mg/kg Ramucirumab

12 mg/kg Ramucirumab

All randomized participants who received at least one dose of study drug and had evaluable PK data. Per protocol, 12 mg/kg Ramucirumab PK data were reported per dose level combining Part A and B participants.

Population Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

Number of Participants With Anti-Ramucirumab Antibodies

Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR)

Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR) or Stable Disease (SD): Disease Control Rate (DCR)

Zero participants analyzed. Duration of response was not evaluable, as there were no participants with CR or PR.

Duration of Response (DOR)

Overall Survival

Participants received 8 milligram per kilogram \[mg/kg\] Ramucirumab administered as an intravenous infusion every 2 weeks (Q2W) with 3 doses per 42 day cycle.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Trial of Everolimus and Bevacizumab in Children With Recurrent Solid Tumors	NCT00756340	Recurrent or Re... CNS Malignancie...	Bevacizumab Everolimus	- 21 Years	St. Jude Children's Research Hospital
A Trial of Everolimus and Bevacizumab in Children With Recurrent Solid Tumors	NCT00756340	Recurrent or Re... CNS Malignancie...	Bevacizumab Everolimus	- 21 Years	St. Jude Children's Research Hospital
A Trial of Everolimus and Bevacizumab in Children With Recurrent Solid Tumors	NCT00756340	Recurrent or Re... CNS Malignancie...	Bevacizumab Everolimus	- 21 Years	St. Jude Children's Research Hospital
A Study of Ramucirumab (LY3009806) in Children With Refractory Solid Tumors	NCT02564198	Pediatric Solid... Refractory Tumo... Recurrent Tumor CNS Malignancie...	Ramucirumab	12 Months - 21 Years	Eli Lilly and Company

Spots Global Cancer Trial Database for cns malignancies