MC# 21-10 - A Dose Escalation and Expansion Study of the Safety and Pharmacokinetics of XL102 as a Single-Agent and Combination Therapy in Subjects with Inoperable Locally Advanced or Metastatic Solid Tumors

  • Agent(s): XL102
  • Disease Type(s): Breast, Prostate, Solid Tumor
  • Phase(s): I
  • Drug Classification(s): Small Molecule, Targeted Therapy
  • Molecular Target(s): CDK7
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Mechanism of Action

XL102 is a selective, and orally bioavailable covalent inhibitor of cyclin-dependent kinase 7 (CDK7), which is a regulator of the cellular transcriptional and cell cycle machinery.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of XL102 alone or in combination with fulvestrant or abiraterone and prednisone
  • How proteins that indicate the status of your disease are affected with use of XL102
  • If XL102 alone or in combination with fulvestrant or abiraterone and prednisone prevents or delays tumor growth or shrinks existing tumors
  • How much of XL102 is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from XL102
Inclusion Criteria
  1. Cytologically or histologically and radiologically confirmed solid tumor that is inoperable, locally advanced, metastatic, or recurrent
    1. Dose-Escalation Stage Cohort A (Solid Tumors): The subject has a solid tumor that is unresectable or metastatic and for which life-prolonging measures do not exist or available therapies are intolerable or no longer effective
    2. Dose-Escalation Stage Cohort B and Cohort-Expansion Stage Cohorts F and H (Hormone Receptor-Positive Breast Cancer): Subjects with breast cancer that is hormone receptor-positive (estrogen receptor positive [ER+] and/or progesterone receptor positive [PR+]) and negative for human epidermal growth factor receptor 2 (HER-2 negative [HER-2-]) and who have documented radiographic disease progression during or following their last systemic anticancer therapy for inoperable locally advanced or metastatic disease
      1. Hormone Receptor-Positive HER-2-Negative Breast Cancer (HR+ BC):
        • Estrogen receptor and progesterone receptor positivity are defined as ≥ 1% of cells expressing hormonal receptors via immunohistochemistry (IHC) analysis
        • HER-2 negativity is defined as either of the following by local laboratory assessments: In situ hybridization (ISH) non-amplified (ratio of HER-2 to CEP17 < 2.0 or single probe average HER-2 gene copy number < 4 signals/cell), or IHC 0 or IHC 1+ (if more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the Sponsor to establish eligibility of the subject)
      2. Subjects must have postmenopausal status due to either surgical/natural menopause or ovarian suppression with gonadotropin-releasing hormone (GnRH) agonist (eg, goserelin)
      3. For all cohorts: Subjects must have received at least one prior endocrine anticancer therapy and one prior CDK4/6 inhibitor therapy either sequentially or concurrently for inoperable locally advanced or metastatic breast cancer
        • Note: There is no limit on the number of prior lines of endocrine anticancer therapy.  Examples include fulvestrant (selective estrogen receptor degrader [SERD]), tamoxifen (selective estrogen receptor modulator [SERM]), exemestane (steroidal aromatase inhibitor [SAI]), and letrozole (non-steroidal aromatase inhibitor [NSAI]).
      4. For Cohort B (Combination Therapy Dose-Escalation Stage): Subjects may have received up to three additional prior lines of systemic anticancer therapy (not including endocrine and CDK4/6 inhibitor therapy) for locally advanced or metastatic disease
      5. For Cohort F and H (Single-Agent and Combination Therapy Cohort-Expansion Stages): Subjects may have received up to two additional prior lines of systemic anticancer therapy (not including endocrine and CDK4/6 inhibitor therapy) for locally advanced or metastatic disease
    3. Dose-Escalation Stage Cohort C and Cohort-Expansion Stage Cohorts G and I (Metastatic Castration-Resistant Prostate Cancer): Subjects with adenocarcinoma of the prostate.  Note: Neuroendocrine differentiation and other histological features are permitted if adenocarcinoma is the primary histology.
      1. Subjects must have progression of prostate cancer documented by either of the following:
        • PSA progression: Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA values from 3 or 4 consecutive assessments with an interval of at least 7 days between assessments.  Note: If qualifying solely by PSA progression, the screening PSA value must be at least 2 ng/mL (2µg/L) and the oldest qualifying value must have been based on a blood sample drawn no longer than one year prior to signing of the informed consent form (ICF) with no change in systemic regimen for the treatment of prostate cancer; up to one PSA decrease is permitted as long as it is not the most recent value.  If the study laboratory is the local laboratory at which the subject’s previous PSA blood samples were drawn, then the screening local lab PSA must be the highest.
        • Radiographic progression in soft-tissue disease.  Note: Subjects with only bone disease must have documented PSA progression in order to be eligible.
      2. For all cohorts: Subjects must have received at least one prior novel hormonal therapy (NHT; eg, enzalutamide, apalutamide, darolutamide, abiraterone, galeterone, orteronel, seviteronel, or equivalent) for castration-sensitive locally advanced (T3 or T4) disease, metastatic prostate cancer (mCSPC), M0 castration-resistant prostate cancer (CRPC), or mCRPC
      3. For Cohort G and I (Cohort Expansion Single Agent and Combination Therapy): Subjects must have received one and only one prior taxane-based chemotherapy (eg, docetaxel, cabazitaxel) for mCRPC
      4. For Cohort C (Combination Therapy Dose-Escalation Stage): Subjects must have received at least one prior taxane-based chemotherapy (eg, docetaxel, cabazitaxel) for mCSPC or mCRPC.  Note: Subjects naïve to taxane-based chemotherapy are eligible for all cohorts if not indicated per Investigator assessment (eg, patient unfit) or patient refusal.
    4. Cohort-Expansion Stage Cohort D (Triple Negative Breast Cancer): Subjects with breast cancer that is negative for HER-2, estrogen receptors, and progesterone receptors, and who have documented radiographic disease progression during or following their last systemic anticancer therapy for inoperable locally advanced or metastatic disease
      1. Triple Negative (ER-/PR-/HER-2-) Breast Cancer:
        • Estrogen receptor and progesterone receptor negativity are defined as < 1% of cells expressing hormonal receptors via IHC analysis
        • HER-2 negativity is defined as either of the following by local laboratory assessments: ISH non-amplified (ratio of HER-2 to CEP17 < 2.0 or single probe average HER-2 gene copy number < 4 signals/cell), or IHC 0 or IHC 1+ (if more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the Sponsor to establish eligibility of the subject)
      2. Subjects must have received at least one line of prior systemic chemotherapy but no more than three lines of prior systemic anticancer therapies for locally advanced or metastatic disease (eg, cytotoxic therapy, targeted therapy, immunotherapy)
    5. Cohort-Expansion Stage Cohort E (Epithelial Ovarian Cancer): Subjects with epithelial ovarian cancer, including primary peritoneal cancer (PPC) and fallopian tube cancer (FTC) who have platinum-resistant disease following treatment with a platinum- containing chemotherapy.  Ovarian borderline epithelial tumors (low malignant potential) are excluded.
      1. Platinum-resistant disease is defined as disease progression between 4 weeks and 6 months after receiving the last platinum dose.  Subjects with platinum- refractory disease (defined as disease progression during platinum-based chemotherapy or within 4 weeks of the last platinum dose) are not eligible.  Note: Subjects who discontinue platinum-based therapy due to an AE cannot be defined as platinum-resistant and are therefore not eligible.
      2. Subjects must have received at least one but not more than three lines of prior systemic anticancer therapy for platinum-resistant ovarian cancer (eg, cytotoxic therapy, targeted therapy, immunotherapy).  Note: Hormone therapy doesn’t count towards the maximum allowed number of lines of prior systemic therapies.
  2. Subjects in the Cohort-Expansion Stage must have measurable disease per RECIST 1.1 as determined by the Investigator.  Note: Measurable disease is not required for subjects in the Dose Escalation Stage.
  3. Tumor tissue material (archival or fresh tumor tissue [if it can be safely obtained]).  Specific requirements for tumor tissue samples will be described in the laboratory manual.  Note: For subjects required to provide tumor tissue prior to and during treatment in the Cohort-Expansion Stage, the pre-treatment tumor tissue sample must have been obtained no more than 60 days before first dose of study treatment.
  4. Recovery to baseline or ≤ Grade 1 severity (Common Terminology Criteria for Adverse Events version 5 [CTCAE v5]) from AEs, unless AEs are clinically nonsignificant (eg, alopecia) or stable (eg, peripheral neuropathy)
  5. Age 18 years or older on the day of consent
  6. ECOG PS of 0-1
  7. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 10 days before first dose of study treatment:
    1. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocyte colony- stimulating factor (G-CSF) support within 2 weeks before screening laboratory sample collection
    2. Platelets ≥ 100,000/mm3 (≥ 100 GI/L)] without transfusion within 2 weeks before screening laboratory sample collection
    3. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 2 weeks before screening laboratory sample collection
    4. Prothrombin time (PT) or activated partial thromboplastin time (aPTT) < 1.2 × upper limit of normal (ULN) or International Normalized Ratio (INR) < 1.5 (for subjects on oral Coumadin-based anticoagulants INR ≤ 3)
    5. ALT, AST, and alkaline phosphatase (ALP) ≤ 3 x ULN (For subjects with mCRPC with documented bone metastases: ALP ≤ 10 x ULN)
    6. Total bilirubin ≤ 1.5 x ULN (for subjects with known Gilbert’s disease ≤ 3 x ULN)
    7. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 45 mL/min (≥ 0.75 mL/sec)] using the Cockcroft-Gault equation
  8. Capable of understanding and complying with the protocol requirements and must have signed the informed consent document
  9. Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception during the course of the study and for 1 month after the last dose of XL102 (and for 3 weeks after the last dose of abiraterone for mCRPC subjects receiving combination therapy).  A barrier contraceptive method (eg, condom) is also required. In addition, men must agree not to donate sperm during these same periods.
  10. Female subjects of childbearing potential must not be pregnant at screening.  Female subjects are considered to be of childbearing potential unless one of the following criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman over 45 years-of-age in the absence of other biological or physiological causes.  In addition, females under 55 years-of-age must have a serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause).  Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.
Exclusion Criteria
  1. Receipt of XL102 or any other selective CDK7 inhibitor
  2. Receipt of any cytotoxic chemotherapy therapy or anticancer antibody therapy (eg, anti- VEGF monoclonal antibody [mAb], programmed cell death protein-1 [PD-1]/programmed death ligand-1 [PD-L1] mAb) including investigational agents within 21 days (42 days for nitrosoureas or mitomycin C) before first dose of study treatment
  3. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitors) within 2 weeks before first dose of study treatment
  4. Receipt of any anticancer hormonal therapy within 2 weeks or within 5 half-lives of the agent, whichever is shorter, before first dose of study treatment. HR+BC subjects enrolled in the Combination Cohorts B and H receiving fulvestrant prior to first dose of study treatment are allowed to continue with their fulvestrant treatment.  Metastatic CRPC subjects enrolled in the Combination Cohorts C and I receiving abiraterone prior to first dose of study treatment are allowed to continue with their abiraterone treatment.  Note: Concomitant use of megestrol acetate or a luteinizing hormone-releasing hormone (LHRH) agonist (eg, leuprolide, goserelin) is permitted.
  5. Radiation therapy within 14 days before first dose of study treatment.  Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
  6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment.  Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
  7. Use of strong inhibitors or inducers of cytochrome P450 (CYP) 3A4, and inhibitors of P- glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporter within 5 half-lives or 4 weeks prior to first dose of study treatment, whichever is shorter
  8. Use of a sensitive substrate of CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or BCRP transporter within 5 half-lives or 4 weeks prior to first dose of study treatment, whichever is shorter.  For subjects with mCRPC in receiving combination treatment with XL102 and abiraterone plus prednisone, use of a substrate of CYP2D6 with a narrow therapeutic index within 5 half-lives or 4 weeks prior to first dose of study treatment, whichever is shorter, is prohibited.
  9. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
    1. Cardiovascular disorders:
      1. Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias (eg, ventricular flutter, ventricular fibrillation, torsades de pointes)
      2. Uncontrolled hypertension defined as sustained blood pressure > 150 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment
      3. Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other ischemic event or pulmonary embolism (PE) within 6 months before first dose.  Note: Subjects with a diagnosis of deep vein thrombosis (DVT) within 6 months before first dose are allowed if managed adequately with anticoagulants and asymptomatic at the time of first dose.
    2. History of any lower gastrointestinal (GI) disorder (such as inflammatory bowel disease [IBD]) or any form of colitis (such as ulcerative colitis or Crohn’s disease)
    3. History of major surgical resection involving the stomach or small bowel or any other reason for a malabsorption syndrome
    4. History of significant bleeding (eg, GI hemorrhage) within 12 weeks before first dose
    5. Active infection (bacterial, viral, or fungal) requiring systemic antimicrobial therapy.  Prophylactic use of antibiotics is allowed.
    6. Known history of COVID-19 unless the subject has clinically recovered from the infection at least 30 days prior to randomization
    7. Moderate to severe hepatic impairment (Child-Pugh B or C)
    8. Requirement for hemodialysis or peritoneal dialysis
    9. History of solid organ, autologous or allogenic stem cell transplant
  10. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 4 weeks before first dose of study treatment.  Minor surgery (eg, fresh tumor biopsy, simple excision, tooth extraction) within 7 days before first dose of study treatment.  Complete wound healing from surgery must have occurred before first dose.  Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
  11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG).  Note: If a single ECG shows a QTcF with an absolute value > 480 ms, two additional ECGs at intervals of approximately 3 minutes must be performed within 30 minutes after the initial ECG, and the average of the three consecutive results for QTcF must be ≤ 480 ms for the subject to be eligible.
  12. History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent
  13. Pregnant or lactating females
  14. Inability to swallow oral study treatment formulation
  15. Previously identified allergy or hypersensitivity to components of the study treatment formulations
  16. Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT04726332

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Re: MC# 21-10