IRB Study Number 25-630
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objectives
• Evaluate the safety and tolerability of ATV-1601 as monotherapy and in combination with fulvestrant
• Determine the MTD and/or RP2D of ATV-1601 as monotherapy and in combination with fulvestrant
Secondary Objectives
• Characterize the PK properties of ATV-1601
• Preliminary assessment of antitumor activity of ATV-1601 as monotherapy and in combination with fulvestrant
Inclusion Criteria
≥ 18 years of age.
Histologically or cytologically confirmed metastatic or advanced-stage solid malignant tumor. Participants with HR+/HER2- breast cancer must have documented histologically confirmed diagnosis of ER+ tumor as per American Society of Clinical Oncologists (ASCO)/College of American Pathologists (CAP) guidelines (Allison et al 2020) assessed locally and defined as ≥ 1% of tumor cells stained positive, and/or progesterone receptor status (positive or negative) as per local assessment and HER2- tumor as per 2018 ASCO/CAP guidelines (Wolff et al 2018) assessed locally.
Have progressed on, were intolerant to, or experienced disease recurrence after standard therapy and, in the opinion of the investigator, have no available effective or tolerable treatment options to derive clinically meaningful benefit. Prior lines including CDK 4/6 inhibitors, PI3K inhibitors, mTOR inhibitors, capivasertib, or other investigational pan-AKT inhibitors are allowed (selective AKT1E17K inhibitors are not allowed). There is no limit to the number of prior lines of therapy for any tumor type.
Tumor must have documented specific mutation profile as outlined below based on local laboratory testing performed on tumor or blood (cfDNA) samples in a Clinical Laboratory Improvement Amendments (CLIA) or similarly certified laboratory and reported in the participant’s medical record. The sponsor medical monitor will be consulted for confirmation of acceptable mutations.
a. Monotherapy escalation, backfill, and dose optimization cohorts: Participants with solid tumors with AKT1E17K mutations. Participants with other AKT1 mutations, activating mutations of PIK3CA, or PTEN LoF may also be enrolled in the dose escalation and dose optimization cohorts with sponsor approval. Backfill will be limited to participants with AKT1E17K mutation solid tumors.
b. Monotherapy expansion Cohort A: Participants with HR+/HER2- breast cancer with AKT1E17K mutations.
c. Monotherapy expansion Cohort B: Participants with other solid tumors with AKT1E17K mutations.
d. Monotherapy expansion Cohort C: Participants with HR+/HER2- breast cancer with activating mutations of PIK3CA or PTEN LoF.
e. Phase 1b combination with fulvestrant (dose escalation and Cohort D): Participants with HR+/HER2- breast cancer with AKT1E17K mutation.
Measurable disease according to RECIST v1.1 criteria. At least 1 measurable lesion that can be measured accurately at screening with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate repeated measurements. OR If no measurable disease is present, then at least 1 predominantly lytic bone lesion or mixed (lytic + sclerotic) bone lesion that can be assessed by CT or MRI must be present. Participants with only sclerotic/osteoblastic bone lesions in the absence of measurable disease are not eligible.
Formalin-fixed paraffin-embedded (FFPE) tumor specimen with sufficient tumor tissue for retrospective confirmation of tumor genetics, which was obtained after the participant’s most recent anticancer therapy, is required from all participants. If such a sample is not available, an older sample is acceptable with sponsor approval. If no tumor tissue is available or if the older sample is not approved by the sponsor, a fresh baseline biopsy may be obtained, if deemed medically feasible and safe.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Women of childbearing potential (WOCP) must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation. A female will be considered to be of childbearing potential unless they have undergone permanent sterilization or are postmenopausal. Postmenopausal is defined as at least 12 months without menses with no other medical reasons (eg, chemical menopause due to anticancer treatment).
For WOCP, agreement must be provided to use a medically approved, highly effective contraceptive method from the time of screening throughout the study for 1 month after administration of the last dose of ATV-1601 and for 2 years after the last dose of fulvestrant (Phase 1b only; or according to locally approved fulvestrant label). Refer to Section 5.7 for acceptable methods of contraception.
All fertile male participants must agree to condom use throughout the study and for 4 months following the last dose of study treatment. Fertile male participants with female partners of childbearing potential must agree to condom use throughout the study and for 4 months following the last dose of study treatment.
Ability to complete all study-required procedures and assessments.
Provision of written informed consent signed and dated by the participant and the investigator before any study-specific interventions are performed.
Exclusion Criteria
Previously documented activating mutations in KRAS, NRAS, HRAS, or BRAF.
Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
a. Absolute neutrophil count (ANC) < 1.0 × 109/L independent of growth factor support for at least 14 days prior to dosing
b. Platelet count < 75 × 109/L independent of platelets transfusion support for at least 7 days prior to dosing
c. Hemoglobin < 9.0 g/dL independent of transfusion support for at least 7 days prior to dosing
d. Estimated glomerular filtration rate (eGFR) < 60 mL/min calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and individualized for participant’s body surface area (BSA) ie, nonindexed GFR = indexed GFR × BSA (m2)/1.73 m2 (Appendix D)
e. Total serum bilirubin > 1.5 × upper limit of normal (ULN) or > 3 × ULN with direct bilirubin > 1.5 × ULN in the presence of Gilbert’s Disease
f. ALT or AST > 3 × ULN if no hepatic metastases are present; > 5 × ULN if liver metastases are present
g. Serum calcium, magnesium, and potassium outside normal reference range for site or CTCAE Grade > 1 with or without supplementation
- Clinically significant abnormalities of glucose metabolism as defined by any of the following:
a. Diagnosis of diabetes mellitus type 1 or 2 (irrespective of management)
b. Screening fasting glucose (FG) value of > 125 mg/dL (9 mmol/L)
c. Glycosylated hemoglobin (HbA1c) > 7.0%
Participants on sodium-glucose luminal cotransporter-2 (SGLT2) inhibitors or glucagon-like peptide 1 receptor agonist for any reason will be excluded from the study, as they will interfere with the assessment for hyperglycemia
Participants who are symptomatic or have uncontrolled brain metastases, leptomeningeal disease, or spinal cord compression not definitively treated with surgery or radiation. Participants with stable brain metastases either previously treated or on treatment with a stable dose of steroids (< 20 mg of prednisone daily or equivalent) or anticonvulsants, with no dose change within 4 weeks before the first dose of study treatment, and no anticipated dose change, are eligible. In the event of steroid taper postradiation therapy, taper must be completed within 2 weeks before the first dose of study treatment.
Any of the following cardiac criteria:
a. Mean resting QTcF > 470 msec regardless of sex obtained from 3 consecutive ECGs
b. Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (eg, complete left bundle branch block, third-degree heart block, Type II second-degree heart block, PR interval > 250 msec)
c. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, potential for torsades de pointes, congenital long QT syndrome, or family history of long QT syndrome
d. 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 Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, or a requirement for anti-arrhythmic medication
e. Cardiac ejection fraction outside normal institutional range or < 50% (whichever is higher) as measured by echocardiogram (ECHO) (or multigated acquisition [MUGA] scan if an ECHO cannot be performed or is inconclusive)
Unable to swallow oral medications or has impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption (eg, active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
Requires necessary treatment with a proton pump inhibitor, histamine-2 receptor antagonists (H2 blockers), or concomitant medication that is a strong or moderate inhibitor or strong inducer of CYP1A2 or CYP3A4/5 enzymes or an inhibitor of BCRP and/or P-gp enzymes/transporters or sensitive substrates of CYP2C8, CYP2C9, CYP2C19, CYP3A, OAT1, OAT3, OATP1B1, OATP1B3, MATE1, or MATE2-K. Individual cases may be discussed with the medical monitor (see Section 5.6 and Appendix C).
Presence or history of any other primary malignancy that has been diagnosed or required therapy within 3 years, other than a history of adequately treated basal or squamous cell carcinoma of the skin, curatively treated localized prostate cancer, or any adequately treated in situ carcinoma.
Major surgery within 4 weeks of the start of ATV-1601 treatment (minor surgical procedures such as central venous catheter placement, tumor biopsy, and feeding tube placement are not considered major).
Received cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or immunotherapy, etc.) or an investigational drug or device within 4 weeks (6 weeks for mitomycin C and nitrosoureas) or 5 half-lives of that agent (whichever is shorter) before the first dose of study treatment. A 10-day washout period is sufficient for participants who have received targeted/palliative radiation.
History of extensive, disseminated, bilateral, or presence of CTCAE Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, or pulmonary fibrosis. Note: Participants with history of prior radiation pneumonitis are NOT excluded.
Known history of severe or uncontrolled systemic diseases, including uncontrolled hypertension, or active infection, including hepatitis B, hepatitis C, and HIV with detectable viral load. Screening for chronic conditions is not required unless mandated by local health authority.
Active or chronic corneal disorders, other active ocular conditions requiring ongoing therapy, or any clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy.
Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment except alopecia, peripheral neuropathy, or ototoxicity, which are excluded if Grade ≥ 3.
Previous allogenic bone marrow or solid organ transplants.
History of hypersensitivity to active or inactive excipients of ATV-1601, fulvestrant, and luteinizing hormone-releasing hormone (LHRH) agonists (if applicable) or drugs with a similar chemical structure or class to ATV-1601, fulvestrant, or LHRH agonists (if applicable).
Use of herbal preparations including but not limited to St. John’s wort, grapefruit juice, pomegranate juice, starfruit, or orange marmalade (made with Seville oranges) from the start of the screening period and during study participation (Section 5.6 and Appendix C).
Pregnant or breastfeeding.
Concurrent participation in another therapeutic, interventional clinical study.
Other severe acute or chronic medical or psychiatric conditions or substance abuse disorders or laboratory abnormality that may increase the risk associated with study participation or study treatment administration, or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study, or could compromise protocol objectives in the opinion of the investigator and/or sponsor.
