Synovial Sarcoma
Conditions
Keywords
soft tissue sarcoma, adolescents and young adults (AYAs), adolescent
Brief summary
This study is being conducted to test the safety and efficacy of ramucirumab in combination with other chemotherapy in the treatment of relapsed, recurrent, or refractory synovial sarcoma (SS) in children and young adults. This trial is part of the CAMPFIRE master protocol (NCT05999994) which is a platform to accelerate the development of new treatments for pediatric and young adult participants with cancer. Your participation in this trial could last 12 months or longer, depending on how you and your tumor respond.
Interventions
DRUGRamucirumab
Ramucirumab given IV
DRUGGemcitabine
Gemcitabine given IV
DRUGDocetaxel
Docetaxel given IV
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to 29 Years
Healthy volunteers
No
Inclusion criteria
* Participants must have discontinued all previous treatments for cancer or investigational agents ≥7 days after the last dose or per the type of previous treatment as stated in the protocol and must have recovered from the acute effects to ≤Grade 2 for alopecia and decreased tendon reflex and to ≤Grade 1 for all other effects at the time of enrollment, unless otherwise noted. Consult with the Lilly clinical research physician or scientist for the appropriate length of time prior to the first dose of study treatment. * Participants with relapsed, recurrent, or refractory SS. * Participants must: * Have measurable disease by Response Evaluation Criteria in Solid Tumors, Version (RECIST) 1.1. * have received at least one prior line of systemic treatment (including neoadjuvant and adjuvant chemotherapy) that contains ifosfamide and/or doxorubicin, or any approved therapies for which they are eligible, unless the patient is not a suitable candidate for the approved therapy. * not be eligible for surgical resection at time of enrollment. * Adequate cardiac function, defined as: Shortening fraction of ≥27% by echocardiogram, or ejection fraction of ≥50% by gated radionuclide study. * Adequate blood pressure (BP) control, defined as: * Participants ≥18 years: Controlled hypertension defined as systolic BP ≤150 millimeters of mercury (mmHg) or diastolic BP ≤90 mmHg where standard medical management is permitted. Please note that ≥2 serial BP readings should be obtained and averaged to determine baseline BP. * Participants \<18 years: A BP ≤95th percentile for age, height, and gender measured as described in National High Blood Pressure Education Program Working Group (NHBPEPWG) on High Blood Pressure in Children and Adolescents (2004), where standard medical management is permitted. Please note that ≥2 serial BP readings should be obtained and averaged to determine baseline BP. * Adequate hematologic function, as defined as: * Absolute neutrophil count (ANC): ≥750/microliters (µL) granulocyte-colony stimulating factor (G-CSF) permitted up to 48 hours prior. Participants with documented history of benign ethnic neutropenia or other conditions could be considered with a lower ANC after discussion with and approval from the Lilly clinical research physician or scientist. * Platelets: ≥75,000/cubic millimeters. Platelet transfusion permitted up to 72 hours prior. * Hemoglobin: ≥8 grams per deciliter (g/dL) (≥80 g/liter). Transfusions to increase the participant's hemoglobin level to at least 8 g/dL are permitted; however, study treatment must not begin until 7 days after the transfusion, and complete blood count criteria for eligibility are confirmed within 24 hr of first study dose. * Adequate renal function, as defined as: * Creatinine clearance or radioscope glomerular filtration rate (GFR) ≥60 milliliters/minute/meters squared OR serum creatinine meeting the following parameters: * for participants ≥18 years of age serum creatinine ≤1.5×upper limit of normal (ULN); * for participants \<18 years of age, serum creatinine based on age/gender as follows: Age 1 to \<2 years maximum serum creatinine 0.6, Age 2 to \<6 years maximum serum creatinine 0.8, Age 6 to \<10 years maximum serum creatinine 1.0, Age 10 to \<13 years maximum serum creatinine 1.2, Age 13 to \<16 years maximum serum creatinine 1.5 for males and 1.4 for females, Age 16 to \<18 years maximum serum creatinine 1.7 for males and 1.4 for females. * Urine protein meeting the following parameters: * for participants ≥18 years of age: \<2+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates proteinuria ≥2+, then a 24-hour urine must be collected and must demonstrate \<2 grams of protein in 24 hours to allow participation in the study. * for participants \<18 years of age: ≤30 milligrams per deciliter urine analysis or \<2+ on dipstick. If urine dipstick or routine analysis indicates proteinuria ≥2+, then a 24-hour urine must be collected and must demonstrate \<1 g of protein in 24 hours to allow participation in the study. * Adequate liver function: * Total bilirubin: ≤1.5×ULN. Except participants with document history of Gilbert Syndrome who must have a total bilirubin level of \<3.0×ULN. * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5×ULN OR ≤5.0×ULN if the liver has tumor involvement. * The participant has an adequate coagulation function as defined by International Normalized Ratio ≤1.5 or prothrombin time ≤1.5×ULN, and partial thromboplastin time ≤1.5×ULN if not receiving anticoagulation therapy. For participants receiving anticoagulants, exceptions to these coagulation parameters are allowed if they are within the intended or expected range for their therapeutic use. Participants must have no history of clinically significant active bleeding (defined as within 14 days of first dose of study drug) or pathological condition that carries a high risk of bleeding (for example, tumor involving major vessels or known esophageal varices). * The participant has adequate hematologic and organ function ≤1 week (7 days) prior to first dose of study drug. * Female participants of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to randomization. Male and female participants must agree to use highly effective contraception for the duration of the study and up to 3 months following the last dose of ramucirumab and 6 months following the last dose of docetaxel and gemcitabine in order to prevent pregnancy.
Exclusion criteria
* Participants with severe and/or uncontrolled concurrent medical disease or psychiatric illness/social situation that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol. * Participants who have active infections requiring therapy. * Participants with an active fungal, bacterial, and/or known severe viral infection including, but not limited to, human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required). * Participants who have had allogeneic bone marrow or solid organ transplant are excluded. * Surgery: Participants who have had, or are planning to have, the following invasive procedures are not eligible: * Major surgical procedure, laparoscopic procedure, or significant traumatic injury within 28 days prior to enrollment. * Central line placement or subcutaneous port placement is not considered major surgery. * Core biopsy, fine needle aspirate, and bone marrow biopsy/aspirate are not considered major surgeries. * Surgical or other wounds must be adequately healed prior to enrollment. * Bleeding and thrombosis: * Participants with evidence of active bleeding or a history of significant (≥Grade 3) bleeding event within 3 months prior to enrollment are not eligible. * Participants with a bleeding diathesis or vasculitis are not eligible. * Participants with known or prior history in the prior 3 months of esophageal varices are not eligible. * Participants with a history of deep vein thrombosis requiring medical intervention (including pulmonary embolism) within 3 months prior to study enrollment are not eligible. * Participants with a history of hemoptysis or other signs of pulmonary hemorrhage within 3 months prior to study enrollment are not eligible. * Cardiac: * Participants with a history of central nervous system (CNS) arterial/venous thromboembolic events (VTEs) including transient ischemic attack (TIA) or cerebrovascular accident (CVA) within 6 months prior to study enrollment are not eligible. * Participants with myocardial infarction or unstable angina within the prior 6 months. * Participants with New York Heart Association Grade 2 or greater congestive heart failure (CHF). * Participants with serious and inadequately controlled cardiac arrhythmia. * Participants with significant vascular disease (eg, aortic aneurysm, history of aortic dissection). * Participants with clinically significant peripheral vascular disease. * Participants who have a history of fistula, gastrointestinal (GI) ulcer or perforation, or intra-abdominal abscess within 3 months of study enrollment are not eligible. * Participants with a history of hypertensive crisis or hypertensive encephalopathy within 6 months of study enrollment are not eligible. * Participants who have non-healing wound, unhealed or incompletely healed fracture, or a compound (open) bone fracture at the time of enrollment are not eligible. * Participants previously treated and progressed on combination gemcitabine and docetaxel regimen. Participants who received combination as maintenance therapy, without progression, would be eligible. * Participants with a known hypersensitivity to ramucirumab, gemcitabine, docetaxel, or agents formulated with Polysorbate 80. * Hepatic impairment: * Severe liver cirrhosis Child-Pugh Class B (or worse). * Cirrhosis with a history of hepatic encephalopathy. * Clinically meaningful ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis. * History of hepatorenal syndrome. * The participant has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (eg, hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea. * The participant has symptomatic interstitial pneumonia or pulmonary fibrosis (or consistent findings of interstitial pneumonia/pulmonary fibrosis on imaging). * Participants with central nervous system (CNS) involvement are ineligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Baseline to Objective Progression or Death Due to Any Cause (Up To 6.4 Months) | PFS is defined as the time from randomization until the first investigator-determined objective progression as defined by Response Evaluation Criteria In Solid Tumors, Version 1.1 (RECIST v1.1) or death from any cause in the absence of progressive disease. Participants known to be alive and without disease progression will be censored at the time of the last adequate tumor assessment or date of randomization, whichever is later. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DoR) | Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up To 4.13 Months) | DoR is defined as the time from the date that measurement criteria for CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent or objective disease progression is observed, per RECIST 1.1 criteria, or the date of death from any cause in the absence of documented disease progression or recurrence. |
| Complete Response (CR): Percentage of Participants Who Achieve CR | Baseline Up to 6.94 months | CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. |
| Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR) | Baseline through Measured Progressive Disease (Up To 6.4 Months) | ORR is the best overall tumor response of complete response (CR) or partial response (PR) as classified by the investigator 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. |
| PK: Minimum Serum Concentration of Ramucirumab (Cmin) | Prior to ramucirumab infusion on Day 8 of Cycle 1, Day 1 of Cycle 2 and Day 1 of Cycle 5 | Cmin was the concentration of study drug in the blood immediately before the next dose was administered. It was measured pre-dose at all visits and was summarized using descriptive statistics. |
| Number of Participants With Treatment-Emergent Anti-Drug Antibodies (TE-ADA) | Baseline Up to 6.94 months | A TE-ADA evaluable participant is considered to be TE-ADA positive if the participant has at least one post baseline titer that is a 4-fold or greater increase in titer from baseline measurement (treatment-boosted). If baseline result is ADA Not Present, then the participant is TE ADA positive if there is at least one post baseline result of ADA Present with titer \>= 20 (treatment-induced). |
| Pharmacokinetics (PK): Maximum Serum Concentration of Ramucirumab (Cmax) | 0.5 hours after the end of ramucirumab infusion on Day 1 of Cycle 1 | Cmax was the concentration of study drug in the blood after the dose is administered. It was measured post-dose and was summarized using descriptive statistics. |
Countries
Australia, Belgium, France, Germany, Italy, Japan, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
Completers included participants who died from any cause.
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab + Gemcitabine + Docetaxel Participants received intravenous infusions of ramucirumab 9 mg/kg, gemcitabine 900 mg/m2 on days 1, 8, and docetaxel 75 mg/m2 on day 8 of a 21-day cycle until disease progression or a criterion for discontinuation were met. | 16 |
| Gemcitabine + Docetaxel Participants received intravenous infusions of gemcitabine 900 mg/m2 on days 1, 8, and docetaxel 75 mg/m2 on day 8 of a 21-day cycle until disease progression or a criterion for discontinuation were met. | 7 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 8 | 3 |
Baseline characteristics
| Characteristic | Ramucirumab + Gemcitabine + Docetaxel | Gemcitabine + Docetaxel | Total |
|---|---|---|---|
| Age, Continuous | 17.70 years STANDARD_DEVIATION 4.22 | 21.40 years STANDARD_DEVIATION 4.58 | 18.80 years STANDARD_DEVIATION 4.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 6 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 5 Participants | 18 Participants |
| Region of Enrollment Australia | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Italy | 5 Participants | 2 Participants | 7 Participants |
| Region of Enrollment Spain | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United Kingdom | 6 Participants | 2 Participants | 8 Participants |
| Region of Enrollment United States | 4 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 10 Participants | 3 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 16 | 4 / 6 |
| other Total, other adverse events | 15 / 16 | 6 / 6 |
| serious Total, serious adverse events | 8 / 16 | 2 / 6 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS is defined as the time from randomization until the first investigator-determined objective progression as defined by Response Evaluation Criteria In Solid Tumors, Version 1.1 (RECIST v1.1) or death from any cause in the absence of progressive disease. Participants known to be alive and without disease progression will be censored at the time of the last adequate tumor assessment or date of randomization, whichever is later.
Time frame: Baseline to Objective Progression or Death Due to Any Cause (Up To 6.4 Months)
Population: All randomized participants (including the censored participants). Number of participants censored in Ramucirumab + Gemcitabine + Docetaxel=4, Gemcitabine + Docetaxel=2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab + Gemcitabine + Docetaxel | Progression Free Survival (PFS) | 2.10 Months |
| Gemcitabine + Docetaxel | Progression Free Survival (PFS) | 2.03 Months |
Comparison: To conclude success for the intervention, the Bayesian analysis must yield a minimum of 99% posterior probability for PFS Hazard ratio less than 1 \[i.e., Pr(HR \< 1) \> 99%\]. The Bayesian analyses below include posterior mean of Hazard ratio, posterior probabilities instead of p-values, and credible intervals instead of confidence intervals.p-value: 0.05180% CI: [1.19, 4.46]Bayesian hierarchical model
Secondary
Complete Response (CR): Percentage of Participants Who Achieve CR
CR is a disappearance of all target and non-target lesions and normalization of tumor marker level.
Time frame: Baseline Up to 6.94 months
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab + Gemcitabine + Docetaxel | Complete Response (CR): Percentage of Participants Who Achieve CR | 0 Percentage of participants |
| Gemcitabine + Docetaxel | Complete Response (CR): Percentage of Participants Who Achieve CR | 0 Percentage of participants |
Secondary
Duration of Response (DoR)
DoR is defined as the time from the date that measurement criteria for CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent or objective disease progression is observed, per RECIST 1.1 criteria, or the date of death from any cause in the absence of documented disease progression or recurrence.
Time frame: Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up To 4.13 Months)
Population: All randomized participants who had CR or PR responses. For Gemcitabine + Docetaxel, there were no participants with CR or PR responses to evaluate DoR, hence, zero participants analysed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab + Gemcitabine + Docetaxel | Duration of Response (DoR) | NA Months |
Secondary
Number of Participants With Treatment-Emergent Anti-Drug Antibodies (TE-ADA)
A TE-ADA evaluable participant is considered to be TE-ADA positive if the participant has at least one post baseline titer that is a 4-fold or greater increase in titer from baseline measurement (treatment-boosted). If baseline result is ADA Not Present, then the participant is TE ADA positive if there is at least one post baseline result of ADA Present with titer \>= 20 (treatment-induced).
Time frame: Baseline Up to 6.94 months
Population: All randomized participants who received at least one dose of study drug and had at least one non-missing baseline, post baseline ADA value.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ramucirumab + Gemcitabine + Docetaxel | Number of Participants With Treatment-Emergent Anti-Drug Antibodies (TE-ADA) | 0 Participants |
| Gemcitabine + Docetaxel | Number of Participants With Treatment-Emergent Anti-Drug Antibodies (TE-ADA) | 0 Participants |
Secondary
Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR)
ORR is the best overall tumor response of complete response (CR) or partial response (PR) as classified by the investigator 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.
Time frame: Baseline through Measured Progressive Disease (Up To 6.4 Months)
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab + Gemcitabine + Docetaxel | Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR) | 6.3 Percentage of participants |
| Gemcitabine + Docetaxel | Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR) | 0 Percentage of participants |
Secondary
Pharmacokinetics (PK): Maximum Serum Concentration of Ramucirumab (Cmax)
Cmax was the concentration of study drug in the blood after the dose is administered. It was measured post-dose and was summarized using descriptive statistics.
Time frame: 0.5 hours after the end of ramucirumab infusion on Day 1 of Cycle 1
Population: All randomized participants who received at least one dose of Ramucirumab and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab + Gemcitabine + Docetaxel | Pharmacokinetics (PK): Maximum Serum Concentration of Ramucirumab (Cmax) | 231 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 43 |
Secondary
PK: Minimum Serum Concentration of Ramucirumab (Cmin)
Cmin was the concentration of study drug in the blood immediately before the next dose was administered. It was measured pre-dose at all visits and was summarized using descriptive statistics.
Time frame: Prior to ramucirumab infusion on Day 8 of Cycle 1, Day 1 of Cycle 2 and Day 1 of Cycle 5
Population: All randomized participants who received at least one dose of Ramucirumab and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab + Gemcitabine + Docetaxel | PK: Minimum Serum Concentration of Ramucirumab (Cmin) | Day 8 of Cycle 1 | 73.3 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 39 |
| Ramucirumab + Gemcitabine + Docetaxel | PK: Minimum Serum Concentration of Ramucirumab (Cmin) | Day 1 of Cycle 2 | 55.4 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 24 |
| Ramucirumab + Gemcitabine + Docetaxel | PK: Minimum Serum Concentration of Ramucirumab (Cmin) | Day 1 of Cycle 5 | NA microgram per milliliter (µg/mL) | — |