Title A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABBV-744 in Subjects with Metastatic Castrate-Resistant Prostate Cancer (CRPC) and Relapsed/Refractory Acute Myeloid Leukemia (AML)


CC 17-1717

Hospital Main Campus

Stage Advanced/Metastatic

Phase Phase 1

Disease Leukemia - Acute Myeloid (AML), Prostate

Drug ABBV-744



Primary Objectives:
  • To determine pharmacokinetics (PK) of ABBV-744
  • To assess the safety and tolerability of ABBV-744
  • To define the dose-limiting toxicity (DLT) of ABBV-744
  • To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RPTD) of ABBV-744 for future drug development
Secondary Study Objective:
  • To evaluate anti-tumor activity as follows:
    • For CRPC:
      • Radiographic Progression Free Survival (rPFS)
      • Time to disease progression (TTP) including all indications of disease progression
      • For subjects with measurable soft tissue and visceral disease only
        • ORR based on RECIST 1.1 (partial response or complete response)
        • Duration of response (DOR)
      • Prostate-specific antigen (PSA) response and time to PSA progression (as per PCWG3).
    • For AML:
      • ORR based on IWG criteria
      • DOR
      • PFS
Inclusion Criteria

Inclusion Criteria

  1. Subject must be ≥ 18 years of age.
  2. Subject must have metastatic CRPC or rel/ref AML not amenable to curative therapy, refractory to standard of care therapy or for which standard of care therapy does not exist. Subjects with AML who are candidates for stem cell transplantation must have been offered this therapeutic option.
    • Metastatic CRPC: adenocarcinoma without neuroendocrine features
      • Must have prostate adenocarcinoma without neuroendocrine features
      • Must have progressed during most recent therapy with androgen synthesis inhibitor (e.g., abiraterone) and/or androgen receptor antagonist (e.g., enzalutamide).
      • Must have evidence of disease progression
    • PSA progression is defined as at least two consecutive rises in serum PSA, obtained at a minimum of 1-week intervals, and each value ≥ 2.0 ng/mL.
    • Radiographic progression is defined for visceral or soft tissue lesions using RECIST 1.1 or appearance of two or more new bone lesions per PCWG3 criteria
      • Must have had prior surgical or chemical castration and serum testosterone of < 50 ng/mL. LHRH agonist/antagonist should be continued if used for castration purposes.
    • Relapsed/refractory AML:
      • Must have morphological/flow cytometry diagnosis of AML other than promyelocytic leukemia (APL).
      • Patients after SCT must have recovered from SCT related toxicities (e.g., no GVHD) and have at least 6 months recovery after allogeneic SCT or 3 months after autologous SCT
      • Relapsed subjects should not be in the first relapse period following a remission period of > 12 months, nor be eligible for standard therapies (e.g., chemotherapy or stem cell transplantation).
      • Refractory subjects should have failed to achieve a CR after ≥ 2 cycles of induction chemotherapy or at least 4 cycles of a hypomethylating agent.
  3. Subject must consent to provide the following for biomarker analyses:
    • All subjects: archived tumor tissue (if available)
    • All subjects with AML: bone marrow aspirates (BMA) pre, on-treatment and at time of recurrence.
  4. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of:
    • Segment 1: 0 - 1
    • Segment 2: 0 - 2
  5. For Segment 1: Subject must have a serum albumin during Screening of ≥ 3.2 g/dL.
  6. Subject has adequate bone marrow, renal and hepatic function as follows:
    • Bone Marrow (for CRPC ONLY)
      • Absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100,000/mm3; Hemoglobin ≥ 9.0 g/dL.
    • Renal Function: Subject has adequate renal function as demonstrated by a calculated creatinine clearance value of ≥ 50 mL/min by the Cockcroft-Gault formula or a creatinine clearance value of ≥ 50 mL/min based on a 24-hour urine collection.
    • Hepatic Function: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN; bilirubin ≤ 1.5 x ULN unless Gilbert's Syndrome is present, then bilirubin may be ≥ 1.5 x ULN but not higher than 2 x ULN. Activated partial thromboplastin time (aPTT) and prothrombin time (PT) not exceed 1.5 x ULN.
  7. If female, subject must be either postmenopausal defined as:
    • Age > 55 years with no menses for 12 or more months without an alternative medical cause.
    • Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an FSH level > 40 IU/L. OR
    • Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). OR
    • For Women of Childbearing Potential:
      • Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control (Section 5.2.4), starting at Study Day 1 through at least 30 days after the last dose of study drug. If the male subject is sexually active, he must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice the protocol specified contraception (Section 5.2.4).
  8. Females of childbearing potential must have a negative serum pregnancy test result at Screening, and a negative urine pregnancy test at Study Day 1. Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as defined above) at Screening do not require pregnancy testing.
  9. Subject must voluntarily sign and date each informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
Exclusion Criteria

Exclusion Criteria

  1. Subject has untreated brain or meningeal metastases. Imaging is not required to rule out brain or meningeal metastases unless there is a clinical suspicion of central nervous system disease. Subjects with treated brain metastases that are radiographically stable for at least 4 weeks after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible, provided that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least 1 week prior to study drug administration). In addition, any AML patient identified, through CSF analysis or imaging, as having active CNS disease, will be excluded from enrollment.
  2. Subject has received anti-cancer traditional medicine or anti-cancer herbal remedies within 14 days prior to ABBV-744 dosing. Saw palmetto is considered anti-cancer herbal remedy. Subject with CRPC who has received anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, biologic or any investigational therapy within a period of 21 days prior to Study Day 1. Subject with AML has received anti-cancer therapy within 14 days or 5 half-lives (whichever is longer; except for patients having received immunotherapy where 21 days is acceptable) prior to Study Day 1. Except for hydroxyurea which will be allowed during screening and treatment for controlling leukocytosis for AML subjects.
  3. Subject has unsolved clinically significant toxicities from most recent prior anticancer therapy, defined as any Common Terminology Criteria for Adverse Events (CTCAE v 4.03) grade 2 or higher toxicity (excluding alopecia).
  4. Subject has received the following within 7 days prior to the first dose of study drug:
    • Corticosteroid therapy for cancer related symptoms;
    • Moderate or strong cytochrome P450 3A (CYP3A) inhibitors such as fluconazole, ketoconazole, and clarithromycin (except for AML subjects who need to take azole-antifungal compounds);
    • Moderate or strong CYP3A inducers such as carbamazepine, phenytoin, and St. John's Wort.
  5. Subject has consumed grapefruit or grapefruit products within 3 days prior to the first dose of study drug.
  6. Subject has had major surgery within 28 days prior to Study Day 1.
  7. Subject has psychiatric illness/social situation that would limit compliance with study requirements.
  8. Subject is unable to swallow or absorb oral tablets.
  9. Subject has known infection with hepatitis B or hepatitis C.
  10. Subject has active peptic ulcer disease or other hemorrhagic esophagitis/gastritis, enteritis, or colitis.
  11. Subject has symptoms of gross hematuria or gross hemoptysis.
  12. Subject has ECG with a QT interval corrected for heart rate using Fridericia's formula (QTcF) > 470 msec or ECG with second degree type 2 or third degree atrioventricular block.
  13. Subject has clinically significant uncontrolled condition(s) that in the opinion of the study Investigator places the subject at an unacceptably high risk for toxicities.
  14. Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study or during the approximately 30 days after the last dose of study drug.
  15. Male subject who is considering fathering a child or donating sperm during the study or during the approximately 90 days after the last dose of study drug.
  16. Subject is prohibited from participating in the study by any law.