Testing AZD5363 as a Potential Targeted Treatment in Cancers With AKT Genetic Changes (MATCH-Subprotocol Y)

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT04439123
• Collaborator: (none)
• Enrollment: 35
• Location: 1
• Arm: 1

Study Details

Study Description

Brief Summary

This phase II MATCH treatment trial identifies the effects of AZD5363 in patients whose cancer has a genetic change called AKT mutation. AZD5363 may block AKT, which is a protein needed for cancer cell growth. Researchers hope to learn if AZD5363 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: Capivasertib	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 capivasertib (AZD5363) orally (PO) twice daily (BID) on days 1-4, 8-11, 15-18, and 22-25. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: MATCH Treatment Subprotocol Y: AZD5363 in Patients With Tumors With AKT Mutations
• Actual Study Start Date: May 31, 2016
• Actual Primary Completion Date: Nov 8, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (capivasertib) Patients receive capivasertib PO BID on days 1-4, 8-11, 15-18, and 22-25. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Capivasertib; Given PO; Other Names: AZD5363

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [Tumor assessments occurred 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 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 rate is determined]

   Progression free survival is defined as time from treatment start date to date of progression or death from any cause, whichever occurs first. 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. 6 month PFS rate was estimated using the Kaplan-Meier method, which can provide a point estimate for any specific time point.

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 an AKT mutation as determined via the MATCH Master Protocol

• Patients with hormone receptor positive, defined as estrogen receptor and/or progesterone receptor > 1% by immunohistochemistry, AND HER2 negative unresectable breast cancer, with no overexpression by immunohistochemistry (IHC) or amplification by in-situ hybridization, are allowed to continue fulvestrant or an aromatase inhibitor (anastrozole, letrozole, exemestane) with AZD5363 if patient just progressed on this anti-estrogen therapy. Gonadotrophin releasing hormone (GnRH) agonists (such as leuprolide or goserelin) are allowed. For instance, if the last treatment was letrozole plus goserelin, the patient is allowed to continue the letrozole plus goserelin with AZD5363

• NOTE: Selective estrogen receptor modulators (SERMs), such as tamoxifen or toremifene, are not allowed, given concerns about CYPD26 and CYP3A4 metabolism, respectively

• 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 with diabetes or risk for hyperglycemia are eligible. Patients with diabetes mellitus may enter the study unless any of the following exclusion criteria are fulfilled:

• Baseline fasting glucose value of > 8.9 mmol/L or 160 mg/dL (fasting is defined as no calorific intake for at least 8 hours)

• Insulin required for routine diabetic management and control

• More than two oral hypoglycemic medications required for routine diabetic management and control

Exclusion Criteria:

• Patients must not have known hypersensitivity to AZD5363 or compounds of similar chemical or biologic composition

• Patients with known KRAS, NRAS, HRAS, or BRAF mutations are not eligible for this protocol, as these mutations may lead to limited response due to resistance

• Patients may not have received treatment with another inhibitor of PI3K, AKT or mTOR in the neoadjuvant, adjuvant or metastatic setting with the exception of FDA approved rapalogs. Patients with metastatic cancer, who received PI3K/AKT/mTOR inhibitors on short preoperative window trials (treatment for 4 weeks or less) will be eligible if the treatment was over 6 months prior to registration

• Patients may not have received strong inhibitors or potent inducers or substrates of CYP3A4 or substrates of CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort)

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: Kevin M Kalinsky, ECOG-ACRIN Cancer Research Group

Study Documents (Full-Text)

• Study Protocol - Jul 10, 2019

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04439123
• Other Study ID Numbers: NCI-2020-02980; NCI-2020-02980; EAY131-Y; EAY131-Y; U10CA180820; U24CA196172
• First Posted: Jun 19, 2020
• Last Update Posted: Jul 19, 2022
• Last Verified: Feb 1, 2022

• Additional relevant MeSH terms: Lymphoma; Neoplasms; Multiple Myeloma; Neoplasms, Plasma Cell

Study Results

Participant Flow

Recruitment Details	Subprotocol Y was activated on May 31, 2016. A total of 43 patients were assigned to this arm after screening, 42 from screening cohort and 1 from outside assay. Of the 43 patients, 35 patients were enrolled to arm Y between July 13, 2016 and August 10, 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 the subprotocol Y, patients had to have an AKT mutation.

Arm/Group Title	Treatment (Capivasertib)
Arm/Group Description	Patients receive capivasertib PO BID on days 1-4, 8-11, 15-18, and 22-25. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Capivasertib: Given PO
Period Title: Overall Study
STARTED	35
COMPLETED	0
NOT COMPLETED	35

Baseline Characteristics

Arm/Group Title	Treatment (Capivasertib)
Arm/Group Description	Patients receive capivasertib PO BID on days 1-4, 8-11, 15-18, and 22-25. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Capivasertib: Given PO
Overall Participants	35
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	30 85.7%
Male	5 14.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 11.4%
Not Hispanic or Latino	30 85.7%
Unknown or Not Reported	1 2.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 5.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 14.3%
White	27 77.1%
More than one race	0 0%
Unknown or Not Reported	1 2.9%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate was defined as the proportion of patients with 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	Tumor assessments occurred 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

Patients who were eligible and received protocol treatment

Arm/Group Title	Treatment (Capivasertib)
Arm/Group Description	Patients receive capivasertib PO BID on days 1-4, 8-11, 15-18, and 22-25. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Capivasertib: Given PO
Measure Participants	35
Number (95% Confidence Interval) [percentage of participants]	28.6 81.7%

2. Secondary Outcome

Title	6-month Progression-free Survival (PFS) Rate
Description	Progression free survival is defined as time from treatment start date to date of progression or death from any cause, whichever occurs first. 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. 6 month PFS rate was estimated using the Kaplan-Meier method, which can provide a point estimate for any specific time point.
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 rate is determined

Outcome Measure Data

Analysis Population Description

Patients who were eligible and received protocol treatment

Arm/Group Title	Treatment (Capivasertib)
Arm/Group Description	Patients receive capivasertib PO BID on days 1-4, 8-11, 15-18, and 22-25. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Capivasertib: Given PO
Measure Participants	35
Number (95% Confidence Interval) [percentage of participants]	50 142.9%

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

Patients who were eligible and received protocol treatment

Arm/Group Title	Treatment (Capivasertib)
Arm/Group Description	Patients receive capivasertib PO BID on days 1-4, 8-11, 15-18, and 22-25. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Capivasertib: Given PO
Measure Participants	35
Median (95% Confidence Interval) [months]	5.5

Adverse Events

Time Frame	Assessed every 28 days while on treatment and for 30 days after the end of treatment, up to 3 years post registration.
Adverse Event Reporting Description	All 35 cases that received protocol treatment were monitored for adverse events.
Arm/Group Title	Treatment (Capivasertib)
Arm/Group Description	Patients receive capivasertib PO BID on days 1-4, 8-11, 15-18, and 22-25. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Capivasertib: Given PO
All Cause Mortality
	Treatment (Capivasertib)
	Affected / at Risk (%)	# Events
Total	23/35 (65.7%)
Serious Adverse Events
	Treatment (Capivasertib)
	Affected / at Risk (%)	# Events
Total	20/35 (57.1%)
Blood and lymphatic system disorders
Anemia	1/35 (2.9%)
Febrile neutropenia	1/35 (2.9%)
Gastrointestinal disorders
Diarrhea	3/35 (8.6%)
Nausea	1/35 (2.9%)
Vomiting	2/35 (5.7%)
Investigations
Alkaline phosphatase increased	1/35 (2.9%)
Aspartate aminotransferase increased	1/35 (2.9%)
Blood bilirubin increased	1/35 (2.9%)
Lymphocyte count decreased	3/35 (8.6%)
Neutrophil count decreased	1/35 (2.9%)
Metabolism and nutrition disorders
Hyperglycemia	9/35 (25.7%)
Hypokalemia	1/35 (2.9%)
Hyponatremia	1/35 (2.9%)
Hypophosphatemia	1/35 (2.9%)
Renal and urinary disorders
Acute kidney injury	1/35 (2.9%)
Proteinuria	1/35 (2.9%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	4/35 (11.4%)
Vascular disorders
Hypertension	1/35 (2.9%)
Other (Not Including Serious) Adverse Events
	Treatment (Capivasertib)
	Affected / at Risk (%)	# Events
Total	29/35 (82.9%)
Blood and lymphatic system disorders
Anemia	4/35 (11.4%)
Gastrointestinal disorders
Abdominal pain	2/35 (5.7%)
Constipation	4/35 (11.4%)
Diarrhea	19/35 (54.3%)
Dry mouth	2/35 (5.7%)
Mucositis oral	4/35 (11.4%)
Nausea	13/35 (37.1%)
Vomiting	6/35 (17.1%)
General disorders
Chills	2/35 (5.7%)
Edema limbs	2/35 (5.7%)
Fatigue	15/35 (42.9%)
Infections and infestations
Urinary tract infection	2/35 (5.7%)
Investigations
Alanine aminotransferase increased	4/35 (11.4%)
Alkaline phosphatase increased	2/35 (5.7%)
Aspartate aminotransferase increased	6/35 (17.1%)
Creatinine increased	2/35 (5.7%)
Lymphocyte count decreased	6/35 (17.1%)
Neutrophil count decreased	2/35 (5.7%)
Platelet count decreased	4/35 (11.4%)
Weight loss	4/35 (11.4%)
White blood cell decreased	6/35 (17.1%)
Metabolism and nutrition disorders
Anorexia	7/35 (20%)
Hyperglycemia	9/35 (25.7%)
Hypomagnesemia	2/35 (5.7%)
Nervous system disorders
Dizziness	3/35 (8.6%)
Headache	3/35 (8.6%)
Renal and urinary disorders
Proteinuria	11/35 (31.4%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	2/35 (5.7%)
Skin and subcutaneous tissue disorders
Dry skin	3/35 (8.6%)
Pruritus	3/35 (8.6%)
Rash acneiform	3/35 (8.6%)
Rash maculo-papular	7/35 (20%)
Skin and subcutaneous tissue disorders - Other, specify	2/35 (5.7%)
Vascular disorders
Hypertension	2/35 (5.7%)

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.