Capivasertib with or without Enzalutamide or Fulvestrant in Treating Patients with Advanced, Metastatic, or Recurrent Solid Tumors with AKT1, AKT2, or AKT3 Mutations
This pilot phase I trial studies how well capivasertib with or without enzalutamide or fulvestrant work in treating patients with solid tumors with AKT1, AKT2, or AKT3 mutations that have spread to other places in the body or have come back. Capivasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Prostate specific antigen or estrogen can cause the growth of tumor cells. Hormone therapy using enzalutamide or fulvestrant may fight prostate or breast cancer by blocking the use of prostate specific antigen or estrogen by the tumor cells. Capivasertib with or without enzalutamide or fulvestrant may work better in treating patients with solid tumor with AKT1, AKT2, or AKT3 mutations.
- Pathologically confirmed recurrent or metastatic advanced solid tumor, for which there is no curative-intent treatment option and confirmation of the presence of AKT1, AKT2, or AKT3 mutations detected by the Memorial Sloan-Kettering (MSK)-integrated mutation profiling of actionable cancer targets (IMPACT) assay platform or other Clinical Laboratory Improvement Act (CLIA)-approved test
- Estrogen receptor positive (ER+) breast cancer patients must have received and progressed on fulvestrant and be post-menopausal
- Prostate cancer patients must have received and progressed on enzalutamide
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- Life expectancy of >= 12 weeks
- Measurable disease as defined by the tumor specific relevant response criteria for the breast and other solid tumor cohorts (measurable disease is not required for enrollment in the prostate cancer cohort): * RECIST version 1.1 criteria * Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria * RANO criteria
- Females should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: * Post-menopausal defined as: ** Aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ** Estradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in post-menopausal range while receiving gonadotrophin releasing hormone (LHRH) analogues for medical castration in patients with breast cancer * Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
- Male patients should be willing to use barrier contraception (i.e. condoms)
- ER+ breast cancer patients harboring the AKT1 E17K mutation (patient population tested in MSK IRB# 14-214, study D3610C00001 part E, ClinicalTrials.gov NCT01226316)
- Diabetes mellitus type 1
- Fasting plasma glucose (fasting is defined as no calorific intake for at least 8 hours): * >= 126 mg/dL for those patients without a pre-existing diagnosis of type 2 diabetes mellitus * >= 167 mg/dL for those patients with a pre-existing diagnosis of type 2 diabetes mellitus
- Glycosylated hemoglobin (HbA1C) >= 8.0%
- Requirement for insulin for routine diabetic management and control
- Requirement for > 2 oral hypoglycemic medications for routine diabetic management and control
- Treatment with any of the following: * Any investigational agents or study drugs from a previous clinical study within 30 days of the first dose of study treatment * Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks or 5 half lives, whichever is shorter, of the first dose of study treatment, except fulvestrant, enzalutamide or hormonal therapy with LHRH analogues for medical castration in patients with breast or prostate cancer, which are permitted * Potent inhibitors or 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) * Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment * Radiotherapy with a wide field of radiation within 4 weeks of the first dose of study treatment * Prior ATP-competitive AKT inhibitors
- With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment
- Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment
- As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus; screening for chronic conditions is not required
- Any of the following cardiac criteria: * Resting corrected QT interval (QTc) > 480 msec obtained from electrocardiogram (ECG) * Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) eg, complete left bundle branch block, third degree heart block * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval * Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association (NYHA) grade >= 2 * Uncontrolled hypotension – systolic blood pressure (BP) < 90 mmHg and/or diastolic BP < 50 mmHg * Left ventricular ejection fraction (LVEF) below lower limit of normal for site
- Absolute neutrophil count < 1 x 10^9/L
- Platelet count < 100 x 10^9/L
- Hemoglobin < 9.0 g/dL
- Alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases, or > 5 times ULN in presence of liver metastases
- Aspartate aminotransferase (AST) > 2.5 times ULN if no demonstrable liver metastases, or > 5 times ULN in presence of liver metastases
- Total bilirubin > 1.5 times ULN (patients with confirmed Gilbert's syndrome may be included in the study)
- Creatinine > 1.5 times ULN concurrent with creatinine clearance < 50 ml/min; confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN
- Proteinuria 3+ on dipstick analysis or > 500 mg/24 hours
- Sodium or potassium outside normal reference range for site
- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5363
- History of hypersensitivity to active or inactive excipients of AZD5363, fulvestrant and enzalutamide or drugs with a similar chemical structure or class to these agents
- Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
Locations & Contacts
Contact: David Michael Hyman
Contact: David Michael Hyman
Contact: David Michael Hyman
Trial Objectives and Outline
I. To determine the objective response rate (ORR) of capivasertib (AZD5363) in patients with advanced solid tumors harboring mutations in AKT1, AKT2, or AKT3, by evaluation of tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1, the Prostate Cancer Working Group 3 (PCWG3), Revised Assessment in Neuro-Oncology (RANO) or prostate-specific antigen (PSA) measurement as applicable.
I. To assess the clinical benefit rate (CBR) (complete response, partial response, or stable disease) at 24 weeks according to according to RECIST v1.1, PCWG3, or RANO as applicable, in patients with advanced solid tumors harboring mutations in AKT1, AKT2, or AKT3.
II. Progression-free survival (PFS) according to RECIST v1.1, PCWG3, or RANO as applicable.
III. Confirm tolerability of AZD5363.
IV. Estimate the proportion of patients without PSA progression by PCWG3 criteria at 24 weeks. (Prostate Cohort)
V. Determine the 12 week PSA response rate (RR). (Prostate Cohort)
VI. Evaluate PSA-PFS by PCWG3 criteria. (Prostate Cohort)
I. Examine the clonality and genetic configuration of the AKT sensitizing mutation in the pretreatment specimens of study patients and their associated clinical response to AZD5363.
II. Examine the pattern of co-mutated genes in AKT-mutant tumors and their association with treatment response or resistance.
III. Describe possible mechanisms of acquired resistance to AKT inhibition.
OUTLINE: Patients are assigned to 1 of 3 cohorts.
COHORT I: Patients with prostate cancer previously treated with enzalutamide receive capivasertib (PO) twice daily (BID) with 4 days on and 3 days off and enzalutamide PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
COHORT II: Patients with estrogen receptor positive breast cancer previously treated with fulvestrant receive capivasertib as in Cohort I and fulvestrant intramuscularly (IM) on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
COHORT III: Patients with other solid tumor receive capivasertib as in Cohort I.
After completion of study treatment, patients are followed up at 28 days.
Trial Phase & Type
Memorial Sloan Kettering Cancer Center
David Michael Hyman
Secondary IDs NCI-2017-01985
Clinicaltrials.gov ID NCT03310541