Carcinoma, Carcinoma, Renal Cell, Enzyme Inhibitors, Kidney Diseases, Kidney Neoplasms, Neoplasms by Site, Protein Kinase Inhibitors, Urologic Neoplasms
Conditions
Keywords
Papillary Renal Cell Cancer, AZD6094, Savolitinib
Brief summary
This study is designed for patients diagnosed with MET-driven, unresectable and locally advanced or metastatic Papillary Renal Cell Carcinoma. The purpose of this study is to see if an investigational new anti-cancer medication, savolitinib, is effective in treating patients with MET-driven PRCC, how it compares with another medication frequently used to treat this disease called sunitinib, and what side effects it might cause.
Interventions
DRUGSavolitinib
600 mg (400 mg if \<50 kg) by mouth (PO) with a meal once daily (QD), continuously
DRUGSunitinib
50 mg by mouth (PO) once daily (QD), with or w/o food, 4 weeks on/2weeks off
Sponsors
AstraZeneca
Hutchison Medipharma Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed PRCC, which is unresectable/locally advanced or metastatic with measurable disease as per RECIST 1.1. Patients with papillary urothelial carcinoma or renal pelvis cancer of the kidney are not considered PRCC and are not eligible. 2. Confirmation of MET-driven PRCC without co-occurring FH or VHL mutations from an FFPE tumour sample using the sponsor-designated central laboratory validated NGS assay 3. Patients who have received no prior systemic therapy as well as those who have received prior systemic therapy for PRCC in the advanced setting.\* Patients can be treatment-naïve, or previously treated, but cannot have previously received sunitinib or a MET inhibitor. Patients who have received prior systemic therapy must have had disease progression in soft tissue disease or bone within 6 months of the last dose of the most recent systemic therapy 4. Adequate haematological, renal, cardiac and liver functions 5. Karnofsky performance status ≥ 80
Exclusion criteria
1. Most recent cytotoxic chemotherapy, immunotherapy, chemo-immunotherapy, or investigational agents \<28 days from the date of randomisation. Most recent non cytotoxic targeted therapy \<14 days from the date of randomisation. 2. Prior treatment with a MET inhibitor (e.g. foretinib, crizotinib, cabozantinib, onartuzumab or previous savolitinib) or sunitinb. 3. Treatment with strong inducers or inhibitors of CYP3A4 or strong inhibitors of CYP1A2, taken within 2 weeks or not possible to be stopped for at least 2 week before the date of randomisation. Herbal medications cannot be taken within 7 days of the date of randomisation (3 weeks for St John's wort). 4. Wide field radiotherapy administered ≤28 days or limited field radiation for palliation ≤7 days prior to the date of randomisation 5. Major surgical procedures ≤28 days of randomisation or minor surgical procedures ≤7 days. No waiting is required following port-a-cath placement. 6. Previously untreated brain metastases 7. Serious active infection or gastrointestinal disease 8. Presence of other active cancers, or history of treatment for invasive cancer within the last 5 years. 9. Mean resting QTcF \>470 msec for women and \>450 msec for men on the Part 2 screening triplicate ECGs or factors that may increase the risk of QTcF prolongation such as chronic hypokalaemia not correctable with supplements, congenital or familial long QT syndrome, or family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) | RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR. | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): \>= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of randomisation until the date of PD (defined by Recist 1.1 and confirmed by BICR) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR. | Time between the date of randomisation and the date of death due to any cause. |
| Objective Response Rate (ORR) by BICR | RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR. | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR prior to progression or any further therapy. |
| Duration of Response (DoR) by BICR | RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR. | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression. |
| Disease Control Rate (DCR) at 6 Months by BICR | RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR. | Disease control rate at 6 months is defined as the percentage of patients who have a best objective response of Complete Response or Partial Response in that period or who have demonstrated Stable Disease for a minimum interval of 23 weeks. |
| Disease Control Rate (DCR) at 12 Months by BICR | RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR. | Disease control rate at 12 months is defined as the percentage of patients who have a best objective response of complete responses or partial responses in that period or who have demonstrated stable disease for a minimum interval of 47 weeks. |
Countries
Brazil, France, Italy, Russia, South Korea, Ukraine, United States
Contacts
PRINCIPAL_INVESTIGATORToni K Choueiri, MD
Dana-Farber Cancer Institute
Participant flow
Recruitment details
First subject enrolled: 25 July 2017. Last subject last visit: 18 August 2019. Data cut off: 19 August 2019. The study was terminated prematurely. Randomized subjects continue to receive IMP as clinically indicated by PI; safety information is being collected for those subjects.
Participants by arm
| Arm | Count |
|---|---|
| Savolitinib QD Savolitinib QD | 33 |
| Sunitinib QD Sunitinib QD | 27 |
| Total | 60 |
Baseline characteristics
| Characteristic | Sunitinib QD | Total | Savolitinib QD |
|---|---|---|---|
| Age, Continuous | 63.1 Years STANDARD_DEVIATION 9.6 | 59.6 Years STANDARD_DEVIATION 12.43 | 56.7 Years STANDARD_DEVIATION 13.81 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 23 Participants | 52 Participants | 29 Participants |
| Sex: Female, Male Female | 10 Participants | 14 Participants | 4 Participants |
| Sex: Female, Male Male | 17 Participants | 46 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 33 | 13 / 27 |
| other Total, other adverse events | 25 / 33 | 27 / 27 |
| serious Total, serious adverse events | 8 / 33 | 8 / 27 |
Outcome results
Primary
Progression Free Survival (PFS) by Blinded Independent Central Review (BICR)
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): \>= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of randomisation until the date of PD (defined by Recist 1.1 and confirmed by BICR) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression.
Time frame: RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR.
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Savolitinib QD | Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) | 7.0 Months |
| Sunitinib QD | Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) | 5.6 Months |
p-value: 0.31395% CI: [0.37, 1.36]Log Rank
Secondary
Disease Control Rate (DCR) at 12 Months by BICR
Disease control rate at 12 months is defined as the percentage of patients who have a best objective response of complete responses or partial responses in that period or who have demonstrated stable disease for a minimum interval of 47 weeks.
Time frame: RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR.
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Savolitinib QD | Disease Control Rate (DCR) at 12 Months by BICR | 30.3 % of participants |
| Sunitinib QD | Disease Control Rate (DCR) at 12 Months by BICR | 22.2 % of participants |
Secondary
Disease Control Rate (DCR) at 6 Months by BICR
Disease control rate at 6 months is defined as the percentage of patients who have a best objective response of Complete Response or Partial Response in that period or who have demonstrated Stable Disease for a minimum interval of 23 weeks.
Time frame: RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR.
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Savolitinib QD | Disease Control Rate (DCR) at 6 Months by BICR | 48.5 % of participants |
| Sunitinib QD | Disease Control Rate (DCR) at 6 Months by BICR | 37.0 % of participants |
Secondary
Duration of Response (DoR) by BICR
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression.
Time frame: RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR.
Population: Duration of Response (DoR) by BICR was calculated for all responders (N=11)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Savolitinib QD | Duration of Response (DoR) by BICR | NA Months |
| Sunitinib QD | Duration of Response (DoR) by BICR | 8.3 Months |
Secondary
Objective Response Rate (ORR) by BICR
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR prior to progression or any further therapy.
Time frame: RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR.
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Savolitinib QD | Objective Response Rate (ORR) by BICR | 27.3 % of participants |
| Sunitinib QD | Objective Response Rate (ORR) by BICR | 7.4 % of participants |
Secondary
Overall Survival (OS)
Time between the date of randomisation and the date of death due to any cause.
Time frame: RECIST tumour assessments every 6 weeks from randomisation until disease progression as defined by Recist 1.1 and confirmed by BICR.
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Savolitinib QD | Overall Survival (OS) | Died | 9 Participants |
| Savolitinib QD | Overall Survival (OS) | Terminated study prior to death | 24 Participants |
| Sunitinib QD | Overall Survival (OS) | Died | 13 Participants |
| Sunitinib QD | Overall Survival (OS) | Terminated study prior to death | 14 Participants |
p-value: 0.1195% CI: [0.21, 1.17]Log Rank