Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Hematopoietic and Lymphoid Cell Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Plasma Cell Myeloma
Conditions
Keywords
FGFR, AZD4547, NCI-MATCH
Brief summary
This phase II MATCH treatment trial identifies the effects of AZD4547 in patients whose cancer has genetic changes called FGFR gene alterations. AZD4547 may stop the growth of cancer cells by blocking FGFR proteins which may be needed for cell growth. Researchers hope to learn if AZD4547 will shrink this type of cancer or stop its growth.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma. SECONDARY OBJECTIVES: I. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma. II. To evaluate time until death or disease progression. III. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms. IV. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens. OUTLINE: Patients receive FGFR inhibitor AZD4547 (AZD4547) orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months if less than 2 years from study entry, and then every 6 months for year 3 from study entry. THE MATCH SCREENING TRIAL: Please see NCT02465060 for information on the MATCH Screening Protocol and applicable documents.
Interventions
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have met applicable eligibility criteria in the Master MATCH Protocol prior to registration to treatment subprotocol * Patients must have FGFR 1-3 mutation or translocation as determined by the MATCH screening assessment * Patients must have an electrocardiogram (ECG) within 8 weeks prior to treatment assignment and must have no clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block) * Patients must have an echocardiogram (ECHO) or a nuclear study (multigated acquisition scan \[MUGA\] or First Pass) within 4 weeks prior to registration to treatment and must not have a left ventricular ejection fraction (LVEF) \< institutional lower limit of normal (LLN). If the LLN is not defined at a site, the LVEF must be \> 50% for the patient to be eligible * Patients must have a pre-study eye exam by an ophthalmologist. Patients with current evidence of corneal or retinal disorder/keratopathy are excluded
Exclusion criteria
* Patients must not have known hypersensitivity to AZD4547 or compounds of similar chemical or biologic composition * Patients must not have received prior FGFR specific inhibitors (e.g. BGJ398, erdafitinib, BAY1163877, LY2874455). Prior non-selective FGFR inhibitor treatment (e.g. pazopanib, dovitinib, ponatinib, brivanib, lucitanib, lenvatinib) will be allowed * Patients must not have any history of or current evidence of renal or endocrine alterations of calcium/phosphate homeostasis, or history of or current evidence of extensive tissue calcification (by evaluation of the clinician), including but not limited to, the soft tissue, kidneys, intestine, myocardium and lung with the exception of calcified lymph nodes and asymptomatic vascular calcification per investigators' judgment * Patients must not be currently using medications that can elevate serum phosphorous and/or calcium levels * Medications that increase serum calcium should be avoided. Over the counter calcium supplements, antacids that contain calcium (Tums) and vitamin D supplements (cholecalciferol and ergocalciferol) should be avoided. Prescription medications including lithium, hydrochlorothiazide and chlorthalidone must be used with caution * Medications that increase serum phosphate should be avoided. Over the counter laxatives that contain phosphate such as Fleets Oral or Fleets enema and Miralax should be avoided
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Assessed at baseline, then every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until disease progression, up to 3 years post registration | Overall response rate was defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) among all eligible and treated patients. Best overall response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. The 90% two-sided binomial exact confidence interval was calculated for ORR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6-month Progression-free Survival (PFS) Rate | Assessed at baseline, then every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until disease progression, up to 3 years post registration, from which 6-month PFS is determined | PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. The 6-month PFS rate was estimated using the Kaplan-Meier method which can provide a point estimate for any specific time point. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. |
| Progression Free Survival (PFS) | Assessed at baseline, then every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until disease progression, up to 3 years post registration | PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. |
Countries
United States
Participant flow
Recruitment details
Subprotocol W was activated on May 31, 2016. 70 patients were assigned to Subprotocol W after screening, all from screening cohort. Of the 70 patients, 52 patients from 47 different sites enrolled in the study between July 2016 and June 2017.
Pre-assignment details
To be assigned to a specific MATCH subprotocol, patients needed to submit a tumor biopsy for molecular characterization and those with molecular variants addressed by treatments included in the trial entered corresponding MATCH subprotocol. For subprotocol W, patients had to have tumors harboring aberrations in FGFR 1-3.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (AZD4547) Patients receive AZD4547 PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
FGFR Inhibitor AZD4547: Given PO | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 12 |
| Overall Study | Clinical concerns for progression and increasing tumor marker | 1 |
| Overall Study | Clinical progression | 1 |
| Overall Study | Death | 2 |
| Overall Study | Disease progression | 25 |
| Overall Study | Ineligible | 2 |
| Overall Study | Never started treatment | 2 |
| Overall Study | Other diseases | 2 |
| Overall Study | Pogression of the lymphadenopathy | 1 |
| Overall Study | Symptomatic decline | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Treatment (AZD4547) |
|---|---|
| Age, Continuous | 61 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 43 Participants |
| Sex: Female, Male Female | 39 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 44 / 52 |
| other Total, other adverse events | 41 / 49 |
| serious Total, serious adverse events | 19 / 49 |
Outcome results
Primary
Overall Response Rate (ORR)
Overall response rate was defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) among all eligible and treated patients. Best overall response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients. The 90% two-sided binomial exact confidence interval was calculated for ORR.
Time frame: Assessed at baseline, then every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until disease progression, up to 3 years post registration
Population: Eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (AZD4547) | Overall Response Rate (ORR) | 8 percentage of participants |
Secondary
6-month Progression-free Survival (PFS) Rate
PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. The 6-month PFS rate was estimated using the Kaplan-Meier method which can provide a point estimate for any specific time point. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients.
Time frame: Assessed at baseline, then every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until disease progression, up to 3 years post registration, from which 6-month PFS is determined
Population: Eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (AZD4547) | 6-month Progression-free Survival (PFS) Rate | 15 percentage of participants |
Secondary
Progression Free Survival (PFS)
PFS was defined as time from treatment start date to date of disease progression or death from any causes, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Disease progression was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1, the Cheson (2014) criteria for lymphoma patients, and the Response Assessment in Neuro-Oncology criteria for glioblastoma patients.
Time frame: Assessed at baseline, then every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until disease progression, up to 3 years post registration
Population: Eligible and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (AZD4547) | Progression Free Survival (PFS) | 3.4 months |