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Dose Escalation Study of Sorafenib and Irinotecan Combination Therapy in Pediatric Patients With Solid Tumors

Primary Purpose

Rhabdomyosarcoma and Other Soft Tissue Sarcomas, Ewing's Sarcoma Family of Tumors, Osteosarcoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
sorafenib
irinotecan
Sponsored by
HMeany
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rhabdomyosarcoma and Other Soft Tissue Sarcomas focused on measuring Sora./Irino. combination therapy

Eligibility Criteria

2 Years - 22 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • AGE: >=2 year and <22 years of age.

    • DIAGNOSIS: solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors and brain tumors.
    • MEASURABLE/EVALUABLE DISEASE: Patients must have measurable or evaluable disease.
    • THERAPEUTIC OPTIONS:
  • The patient's cancer must have relapsed after or failed to respond to frontline curative therapy and there must not be other potentially curative treatment options available. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities.

    • PRIOR THERAPY:

  • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrolling on this study.
  • No limitation on the number of prior chemotherapy regimens that the patient may have received prior to study enrollment.
  • Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs must be at least 3 weeks prior to study entry.
  • Immunotherapy: The last dose of immunotherapy (monoclonal antibody or vaccine) must be at least 4 weeks prior to study entry.
  • Biologic (anti-cancer agent): The last dose of all biologic agents for the treatment of the patient's cancer (such as retinoids or tyrosine kinase inhibitors) must be at least 7 days prior to study entry. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
  • Investigational anti-cancer agent: The last dose of all investigational agents must be at least 30 days prior to study entry.
  • Radiation therapy: The last dose of radiation to more than 25% of marrow containing bones (pelvis, spine, skull) must be at least 4 weeks prior to study entry. The last dose of all other local palliative (limited port) radiation must be at least 2 weeks prior to study entry.
  • Stem Cell Transplantation. At least 2 months post-autologous stem cell transplant or at least 3 months post-allogeneic transplant and recovered from toxicities without evidence of graft versus host disease.
  • Prior camptothecins: Patients who previously received irinotecan as front line treatment or in an adjuvant setting are eligible if they did not experience severe toxicities (defined as grade 4 non-hematologic toxicity or failure to recover from any non-hematologic or hematologic toxicity within 6 weeks of receiving the drug) possibly, probably or definitely related to the agent, and they did not experience tumor progression during the time they received the agent. Patients who previously received topotecan are eligible.
  • Growth Factors. The last dose of colony stimulating factors, such as filgrastim, sargramostim, and erythropoietin, must be at least 1 week prior to study entry, the last dose of long-acting colony stimulating factors, such as pegfilgrastim, must be at least 2 weeks prior to study entry.

    • CONCURRENT THERAPIES:

  • No other anti-cancer therapy (chemotherapy, biological therapy, radiation therapy) is permitted.

    • PERFORMANCE STATUS:

  • Patients > 10 years old must have a Karnofsky performance level >= 50%, and children <= 10 years old must have a Lansky performance level >= 50%.
  • Patients who are unable to walk because of paralysis or motor weakness, but who are up in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.

    • HEMATOLOGIC FUNCTION:

  • Peripheral absolute neutrophil count (ANC) of >=750/mcL
  • Platelet count >=75,000/mcL without administration of platelets

    • HEPATIC FUNCTION:

  • Total bilirubin must be gender
  • SGPT (ALT) must be - Serum albumin >/= 2 g/dL

    • RENAL FUNCTION: Age-adjusted normal serum creatinine (see table below) OR a creatinine clearance >=60 mL/min/1.73 m2. Age Maximum Serum Creatinine (Years) (mg/dl) Male Female 2 to less than 6 years 0.8 0.8 6 to less than 10 years 1 1 10 to less than 13 years 1.2 1.2 13 years to less than 16 years 1.5 1.4 Greater than or equal to 16 years 1.7 1.4 The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR (Schwartz et.al. J Peds 106:522, 1985) utilizing child length and stature data published by the CDC.
    • ADEQUATE PULMONARY FUNCTION: Defined as no dyspnea at rest, no exercise intolerance, and a pulse oximetry >94% on room air if there is clinical indication for determination (cough, etc).
    • Normal serum amylase and lipase
    • PT and PTT <= 1.5 times the upper limit of normal for age (including patients on prophylactic anticoagulation). Prophylactic anticoagulation as described below is permitted:
    • Low dose warfarin with PT-INR <= 1.5 x ULN. For subjects receiving warfarin, the PT-INR should be measured prior to initiation of trial drugs and should be monitored at least weekly, or as defined by the local standard of care, until it is stable.
    • Low-dose aspirin (<= 100 mg daily).
    • Prophylactic doses of heparin.
    • Blood pressure (BP) <= the 95th percentile for age, height and gender and not receiving anti-hypertensive medications or well controlled on antihypertensive medications for one week. Blood pressure will be recorded as the average of 2 measurements separated by at least 2 minutes. If the second value is more than 5 mmHg different from the first, continued measurements should be made every 2 minutes until a stable value is attained. The recorded value should be the average of the last two measurements obtained. Blood pressure is to be measured preferably in the right arm with an appropriate sized cuff, taken in a seated position after 3 minutes of rest. Oscillometric blood pressure measurements that exceed the 95th percentile should be confirmed by auscultation.
    • BIRTH CONTROL: Patients of childbearing or child-fathering potential will be required and must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study.

Exclusion Criteria:

  • Clinically significant unrelated systemic illness, such as serious infections, hepatic,renal or other organ dysfunction, which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate the agents used in this trial or are likely to interfere with the study procedures or results.

    • Patients with known intra-axial metastatic central nervous system lesions.
    • Pregnant or breast-feeding females are excluded because of the potential harmful effects of sorafenib and irinotecan on a developing fetus or nursing child.
    • Patients currently receiving other anticancer agents or radiation therapy.
    • Patients currently receiving other investigational agents.
    • Prior treatment with a sorafenib containing regimen.
    • Inability to swallow pills.
    • Evidence of bleeding diathesis and/or on therapeutic anti-coagulation medications.
    • Patients with known Gilbert syndrome.
    • Patients who take cytochrome P450 enzyme-inducing antiepileptic agents (phenytoin, carbamazepine, phenobarbitol), rifampin, erythromycin, azithromycin, azole antifungals, grape fruit juice or St. Johns Wort. Patients must have discontinued these medications at least 7 days prior to enrollment of trial.
    • Patients with baseline hypertension (>=95th BP percentile for age, height and gender) and not controlled on anti-hypertensive medications.
    • Patients with a malabsorption syndrome.
    • Patients with known human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection.
    • Patients with serious non-healing wound, ulcer, or bone fracture.
    • Patients with thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
    • Patients with cardiac ventricular arrhythmias requiring anti-arrhythmic therapy,unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months
    • Patients who have undergone major surgery, open biopsy or significant traumatic injury within 4 weeks of study enrollment.
    • Patients with known or suspected allergy to any agent given in the course of this trial.

Sites / Locations

  • Children's National Medical Center
  • National Cancer Institute
  • Children's Hospital Boston/Dana-Farber Cancer Institute
  • The Children's Hospital of Philadelphia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Combination Therapy

Arm Description

Three to 6 patient will be enrolled at each dose level and dose escalations will proceed in the absence of dose-limiting toxicity attributed to therapy, first with dose escalation of sorafenib and then, if tolerated, escalation of irinotecan.

Outcomes

Primary Outcome Measures

Toxicity Profile
Determine the toxicity profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of sorafenib, when administered in combination with oral irinotecan in children with relapsed or refractory solid tumors.
Patient Related Outcomes
Demonstrate the feasibility of incorporating measurement of patient-related outcome into a four site phase 1 trial of sorafenib and irinotecan for children and adolescents. Demonstrate feasibility: defined as 70% of participants will complete the 5 patient-reported outcomes (PROs) (pain, fatigue, worry, sadness and physical functioning) at both baseline (pre-treatment) and at the end of the first course and missing data will not be greater than 15% across the 5 PROs at either data point.

Secondary Outcome Measures

Pharmacokinetic Profile
Describe the plasma pharmacokinetic profile of sorafenib and irinotecan when administered as combination therapy in children and adolescents.
Disease Evaluation
Evaluate disease response, based on criteria for measurable lesions (RECIST) and evaluable lesions, to guide further development in phase 2 studies.
Integration of Patient Related Outcomes with other outcome measures
Correlate and integrate the PRO scores with traditional endpoints of toxicity, pharmacokinetic profile, and tumor response associated with the sorafenib and irinotecan combination.

Full Information

First Posted
January 4, 2012
Last Updated
February 26, 2015
Sponsor
HMeany
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1. Study Identification

Unique Protocol Identification Number
NCT01518413
Brief Title
Dose Escalation Study of Sorafenib and Irinotecan Combination Therapy in Pediatric Patients With Solid Tumors
Official Title
Phase 1 Dose Escalation Study of Sorafenib and Irinotecan Combination Therapy in Pediatric Patients With Relapsed or Refractory Solid Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
February 2015
Overall Recruitment Status
Completed
Study Start Date
December 2011 (undefined)
Primary Completion Date
January 2015 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
HMeany

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine the safest and most effective oral dose combinations of sorafenib and irinotecan in pediatric patients with solid tumors, i.e. relapsed or refractory.
Detailed Description
Sorafenib, a multi-kinase inhibitor of several targets felt to be important in tumor growth and angiogenesis, has been well studied and shown promising clinical results in adult cancer patients and the Maximum Tolerated Dose or MTD has been determined in pediatric patients. Irinotecan is known to be effective and is widely used in pediatric malignancies. The combination of sorafenib with irinotecan is of interest as these agents have different mechanisms of action. In addition, the combination has been evaluated in adult patients and deemed tolerable without alterations in the pharmacokinetic (PK) profile at the MTD. The trial we are proposing also offers the advantage of being a completely oral regimen, adding convenience and cost effectiveness. Given these considerations, if the sorafenib/irinotecan combination proves tolerable in phase I studies and shows efficacy in phase II studies, it would be an attractive combination to incorporate into existing chemotherapy regimens for pediatric cancer.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rhabdomyosarcoma and Other Soft Tissue Sarcomas, Ewing's Sarcoma Family of Tumors, Osteosarcoma, Neuroblastoma, Brain Tumors
Keywords
Sora./Irino. combination therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
17 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Combination Therapy
Arm Type
Experimental
Arm Description
Three to 6 patient will be enrolled at each dose level and dose escalations will proceed in the absence of dose-limiting toxicity attributed to therapy, first with dose escalation of sorafenib and then, if tolerated, escalation of irinotecan.
Intervention Type
Drug
Intervention Name(s)
sorafenib
Intervention Description
sorafenib (50 and 200 mg tablets) orally twice daily, on a continuous schedule at a starting dose of 150mg/m2/dose.
Intervention Type
Drug
Intervention Name(s)
irinotecan
Intervention Description
irinotecan (70 mg/m2/dose) orally, concurrently, once daily,starting at the beginning of the 21 day cycle,repeated every 21 days
Primary Outcome Measure Information:
Title
Toxicity Profile
Description
Determine the toxicity profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of sorafenib, when administered in combination with oral irinotecan in children with relapsed or refractory solid tumors.
Time Frame
24 months
Title
Patient Related Outcomes
Description
Demonstrate the feasibility of incorporating measurement of patient-related outcome into a four site phase 1 trial of sorafenib and irinotecan for children and adolescents. Demonstrate feasibility: defined as 70% of participants will complete the 5 patient-reported outcomes (PROs) (pain, fatigue, worry, sadness and physical functioning) at both baseline (pre-treatment) and at the end of the first course and missing data will not be greater than 15% across the 5 PROs at either data point.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Pharmacokinetic Profile
Description
Describe the plasma pharmacokinetic profile of sorafenib and irinotecan when administered as combination therapy in children and adolescents.
Time Frame
24 months
Title
Disease Evaluation
Description
Evaluate disease response, based on criteria for measurable lesions (RECIST) and evaluable lesions, to guide further development in phase 2 studies.
Time Frame
24 months
Title
Integration of Patient Related Outcomes with other outcome measures
Description
Correlate and integrate the PRO scores with traditional endpoints of toxicity, pharmacokinetic profile, and tumor response associated with the sorafenib and irinotecan combination.
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
22 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: AGE: >=2 year and <22 years of age. DIAGNOSIS: solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors and brain tumors. MEASURABLE/EVALUABLE DISEASE: Patients must have measurable or evaluable disease. THERAPEUTIC OPTIONS: The patient's cancer must have relapsed after or failed to respond to frontline curative therapy and there must not be other potentially curative treatment options available. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities. • PRIOR THERAPY: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrolling on this study. No limitation on the number of prior chemotherapy regimens that the patient may have received prior to study enrollment. Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs must be at least 3 weeks prior to study entry. Immunotherapy: The last dose of immunotherapy (monoclonal antibody or vaccine) must be at least 4 weeks prior to study entry. Biologic (anti-cancer agent): The last dose of all biologic agents for the treatment of the patient's cancer (such as retinoids or tyrosine kinase inhibitors) must be at least 7 days prior to study entry. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair. Investigational anti-cancer agent: The last dose of all investigational agents must be at least 30 days prior to study entry. Radiation therapy: The last dose of radiation to more than 25% of marrow containing bones (pelvis, spine, skull) must be at least 4 weeks prior to study entry. The last dose of all other local palliative (limited port) radiation must be at least 2 weeks prior to study entry. Stem Cell Transplantation. At least 2 months post-autologous stem cell transplant or at least 3 months post-allogeneic transplant and recovered from toxicities without evidence of graft versus host disease. Prior camptothecins: Patients who previously received irinotecan as front line treatment or in an adjuvant setting are eligible if they did not experience severe toxicities (defined as grade 4 non-hematologic toxicity or failure to recover from any non-hematologic or hematologic toxicity within 6 weeks of receiving the drug) possibly, probably or definitely related to the agent, and they did not experience tumor progression during the time they received the agent. Patients who previously received topotecan are eligible. Growth Factors. The last dose of colony stimulating factors, such as filgrastim, sargramostim, and erythropoietin, must be at least 1 week prior to study entry, the last dose of long-acting colony stimulating factors, such as pegfilgrastim, must be at least 2 weeks prior to study entry. • CONCURRENT THERAPIES: No other anti-cancer therapy (chemotherapy, biological therapy, radiation therapy) is permitted. • PERFORMANCE STATUS: Patients > 10 years old must have a Karnofsky performance level >= 50%, and children <= 10 years old must have a Lansky performance level >= 50%. Patients who are unable to walk because of paralysis or motor weakness, but who are up in a wheelchair will be considered ambulatory for the purpose of calculating the performance score. • HEMATOLOGIC FUNCTION: Peripheral absolute neutrophil count (ANC) of >=750/mcL Platelet count >=75,000/mcL without administration of platelets • HEPATIC FUNCTION: Total bilirubin must be gender SGPT (ALT) must be - Serum albumin >/= 2 g/dL RENAL FUNCTION: Age-adjusted normal serum creatinine (see table below) OR a creatinine clearance >=60 mL/min/1.73 m2. Age Maximum Serum Creatinine (Years) (mg/dl) Male Female 2 to less than 6 years 0.8 0.8 6 to less than 10 years 1 1 10 to less than 13 years 1.2 1.2 13 years to less than 16 years 1.5 1.4 Greater than or equal to 16 years 1.7 1.4 The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR (Schwartz et.al. J Peds 106:522, 1985) utilizing child length and stature data published by the CDC. ADEQUATE PULMONARY FUNCTION: Defined as no dyspnea at rest, no exercise intolerance, and a pulse oximetry >94% on room air if there is clinical indication for determination (cough, etc). Normal serum amylase and lipase PT and PTT <= 1.5 times the upper limit of normal for age (including patients on prophylactic anticoagulation). Prophylactic anticoagulation as described below is permitted: Low dose warfarin with PT-INR <= 1.5 x ULN. For subjects receiving warfarin, the PT-INR should be measured prior to initiation of trial drugs and should be monitored at least weekly, or as defined by the local standard of care, until it is stable. Low-dose aspirin (<= 100 mg daily). Prophylactic doses of heparin. Blood pressure (BP) <= the 95th percentile for age, height and gender and not receiving anti-hypertensive medications or well controlled on antihypertensive medications for one week. Blood pressure will be recorded as the average of 2 measurements separated by at least 2 minutes. If the second value is more than 5 mmHg different from the first, continued measurements should be made every 2 minutes until a stable value is attained. The recorded value should be the average of the last two measurements obtained. Blood pressure is to be measured preferably in the right arm with an appropriate sized cuff, taken in a seated position after 3 minutes of rest. Oscillometric blood pressure measurements that exceed the 95th percentile should be confirmed by auscultation. BIRTH CONTROL: Patients of childbearing or child-fathering potential will be required and must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study. Exclusion Criteria: Clinically significant unrelated systemic illness, such as serious infections, hepatic,renal or other organ dysfunction, which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate the agents used in this trial or are likely to interfere with the study procedures or results. Patients with known intra-axial metastatic central nervous system lesions. Pregnant or breast-feeding females are excluded because of the potential harmful effects of sorafenib and irinotecan on a developing fetus or nursing child. Patients currently receiving other anticancer agents or radiation therapy. Patients currently receiving other investigational agents. Prior treatment with a sorafenib containing regimen. Inability to swallow pills. Evidence of bleeding diathesis and/or on therapeutic anti-coagulation medications. Patients with known Gilbert syndrome. Patients who take cytochrome P450 enzyme-inducing antiepileptic agents (phenytoin, carbamazepine, phenobarbitol), rifampin, erythromycin, azithromycin, azole antifungals, grape fruit juice or St. Johns Wort. Patients must have discontinued these medications at least 7 days prior to enrollment of trial. Patients with baseline hypertension (>=95th BP percentile for age, height and gender) and not controlled on anti-hypertensive medications. Patients with a malabsorption syndrome. Patients with known human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection. Patients with serious non-healing wound, ulcer, or bone fracture. Patients with thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months. Patients with cardiac ventricular arrhythmias requiring anti-arrhythmic therapy,unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months Patients who have undergone major surgery, open biopsy or significant traumatic injury within 4 weeks of study enrollment. Patients with known or suspected allergy to any agent given in the course of this trial.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Holly Meany, MD
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
National Cancer Institute
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Children's Hospital Boston/Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
The Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
34383370
Citation
Meany HJ, Widemann BC, Hinds PS, Bagatell R, Shusterman S, Stern E, Jayaprakash N, Peer CJ, Figg WD, Hall OM, Sissung TM, Kim A, Fox E, London WB, Rodriguez-Galindo C, Minturn JE, Dome JS. Phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors. Pediatr Blood Cancer. 2021 Nov;68(11):e29282. doi: 10.1002/pbc.29282. Epub 2021 Aug 12.
Results Reference
derived

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Dose Escalation Study of Sorafenib and Irinotecan Combination Therapy in Pediatric Patients With Solid Tumors

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