Testing AZD4547 as a Potential Targeted Treatment in Cancers With FGFR Genetic Changes (MATCH-Subprotocol W)

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT04439240
• Collaborator: (none)
• Enrollment: 52
• Location: 1
• Arm: 1
• Actual Duration (Months): 49
• Patients Per Site Per Month: 1.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Lymphoma; Advanced Malignant Solid Neoplasm; Hematopoietic and Lymphoid Cell Neoplasm; Refractory Lymphoma; Refractory Malignant Solid Neoplasm; Refractory Plasma Cell Myeloma	Drug: FGFR Inhibitor AZD4547	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. 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:

1. 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.

2. 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.

3. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: MATCH Treatment Subprotocol W: Phase II Study of AZD4547 in Patients With Tumors With Aberrations in the FGFR Pathway
• Actual Study Start Date: May 31, 2016
• Actual Primary Completion Date: Jun 6, 2019
• Actual Study Completion Date: Jun 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: FGFR Inhibitor AZD4547; Given PO; Other Names: AZD4547

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ECOG-ACRIN Cancer Research Group	Philadelphia	Pennsylvania	United States	19103

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Young Kwang Chae, ECOG-ACRIN Cancer Research Group

Study Documents (Full-Text)

• Study Protocol - May 16, 2018

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04439240
• Other Study ID Numbers: NCI-2020-03213; NCI-2020-03213; EAY131-W; EAY131-W; U10CA180820; U24CA196172
• First Posted: Jun 19, 2020
• Last Update Posted: Jun 29, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by National Cancer Institute (NCI): FGFR; AZD4547; NCI-MATCH
• Additional relevant MeSH terms: Lymphoma; Neoplasms; Multiple Myeloma; Neoplasms, Plasma Cell

Study Results

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 Detail	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.

Arm/Group Title	Treatment (AZD4547)
Arm/Group Description	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
Period Title: Overall Study
STARTED	52
Started Protocol Therapy	50
Eligible	49
Eligible and Started Protocol Therapy	48
Reported Adverse Events Data	49
COMPLETED	0
NOT COMPLETED	52

Baseline Characteristics

Arm/Group Title	Treatment (AZD4547)
Arm/Group Description	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
Overall Participants	48
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	39 81.3%
Male	9 18.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 6.3%
Not Hispanic or Latino	42 87.5%
Unknown or Not Reported	3 6.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 2.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	43 89.6%
More than one race	0 0%
Unknown or Not Reported	4 8.3%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	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

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Treatment (AZD4547)
Arm/Group Description	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
Measure Participants	48
Number (90% Confidence Interval) [percentage of participants]	8 16.7%

2. Secondary Outcome

Title	6-month Progression-free Survival (PFS) Rate
Description	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

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Treatment (AZD4547)
Arm/Group Description	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
Measure Participants	48
Number (90% Confidence Interval) [percentage of participants]	15 31.3%

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	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

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Treatment (AZD4547)
Arm/Group Description	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
Measure Participants	48
Median (95% Confidence Interval) [months]	3.4

Adverse Events

Time Frame	Assessed every 28 days while on treatment and for 30 days after the end of treatment, up to 3 years
Adverse Event Reporting Description	All 52 patients enrolled to the trial were monitored for mortality. Of the 50 patients who received protocol therapy, 49 were evaluable for AEs (1 patient had no toxicity data)
Arm/Group Title	Treatment (AZD4547)
Arm/Group Description	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
All Cause Mortality
	Treatment (AZD4547)
	Affected / at Risk (%)	# Events
Total	44/52 (84.6%)
Serious Adverse Events
	Treatment (AZD4547)
	Affected / at Risk (%)	# Events
Total	19/49 (38.8%)
Blood and lymphatic system disorders
Anemia	2/49 (4.1%)
Febrile neutropenia	1/49 (2%)
Eye disorders
Dry eye	1/49 (2%)
Gastrointestinal disorders
Abdominal pain	1/49 (2%)
Constipation	1/49 (2%)
Esophageal pain	1/49 (2%)
Mucositis oral	7/49 (14.3%)
Small intestinal obstruction	1/49 (2%)
Infections and infestations
Sepsis	1/49 (2%)
Investigations
Alanine aminotransferase increased	3/49 (6.1%)
Aspartate aminotransferase increased	4/49 (8.2%)
GGT increased	1/49 (2%)
Neutrophil count decreased	1/49 (2%)
Metabolism and nutrition disorders
Hypoalbuminemia	1/49 (2%)
Hyponatremia	1/49 (2%)
Hypophosphatemia	1/49 (2%)
Nervous system disorders
Dizziness	1/49 (2%)
Peripheral sensory neuropathy	1/49 (2%)
Syncope	1/49 (2%)
Respiratory, thoracic and mediastinal disorders
Laryngeal mucositis	1/49 (2%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	3/49 (6.1%)
Other (Not Including Serious) Adverse Events
	Treatment (AZD4547)
	Affected / at Risk (%)	# Events
Total	41/49 (83.7%)
Blood and lymphatic system disorders
Anemia	9/49 (18.4%)
Eye disorders
Blurred vision	6/49 (12.2%)
Dry eye	12/49 (24.5%)
Eye disorders - Other, specify	10/49 (20.4%)
Gastrointestinal disorders
Constipation	12/49 (24.5%)
Diarrhea	10/49 (20.4%)
Dry mouth	21/49 (42.9%)
Dyspepsia	3/49 (6.1%)
Gastroesophageal reflux disease	4/49 (8.2%)
Mucositis oral	17/49 (34.7%)
Nausea	12/49 (24.5%)
Vomiting	11/49 (22.4%)
General disorders
Fatigue	19/49 (38.8%)
Investigations
Alanine aminotransferase increased	6/49 (12.2%)
Alkaline phosphatase increased	10/49 (20.4%)
Aspartate aminotransferase increased	5/49 (10.2%)
Blood bilirubin increased	3/49 (6.1%)
Creatinine increased	6/49 (12.2%)
Lymphocyte count decreased	5/49 (10.2%)
Neutrophil count decreased	3/49 (6.1%)
Weight loss	7/49 (14.3%)
White blood cell decreased	6/49 (12.2%)
Metabolism and nutrition disorders
Anorexia	13/49 (26.5%)
Hypercalcemia	6/49 (12.2%)
Hypomagnesemia	3/49 (6.1%)
Hyponatremia	5/49 (10.2%)
Hypophosphatemia	3/49 (6.1%)
Nervous system disorders
Dysgeusia	10/49 (20.4%)
Peripheral sensory neuropathy	3/49 (6.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	5/49 (10.2%)
Nasal congestion	3/49 (6.1%)
Skin and subcutaneous tissue disorders
Alopecia	14/49 (28.6%)
Dry skin	9/49 (18.4%)
Nail discoloration	7/49 (14.3%)
Nail loss	6/49 (12.2%)
Palmar-plantar erythrodysesthesia syndrome	7/49 (14.3%)
Pruritus	3/49 (6.1%)
Skin and subcutaneous tissue disorders - Other, specify	4/49 (8.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.