Patient case: 45-year-old female with cervical cancer; genetic feature: ERBB2 (S310Y)

Clinical trial: Venetoclax and Quizartinib in Treating Patients With FLT3-mutated Recurrent or Refractory Acute Myeloid Leukemia

Summary: This clinical research study has 2 parts: Phase 1b and Phase 2.
  The goal of Phase 1b of this clinical research study is to find the highest, tolerable dose and the recommended Phase 2 dose of quizartinib that can be combined with venetoclax and given to patients with acute myelogenous leukemia (AML).
  The goal of Phase 2 of this clinical research study is to study the effectiveness of the recommended Phase 2 dose combination in AML patients.
  The safety of the study drug combination will be studied in both parts.
  This is an investigational study. Venetoclax is FDA approved and commercially available to treat other types of leukemia. Quizartinib (by itself and in combination with venetoclax) is not FDA approved or commercially available. At this time, the drug combination is being used for research purposes only. The study doctor can explain how the study drugs are designed to work.
  Up to 32 participants will be enrolled in this study. All will take part at MD Anderson.


Eligibility: Inclusion Criteria:
  1. FLT3-ITD mutated patients with relapsed/refractory AML (up to two prior therapeutic regimens for AML i.e. up to salvage 2 AML), including patients who may have been previously exposed to prior FLT3-inhibitor/s other than quizartinib (SCT or stem cell therapy for patients who previously underwent SCT/stem cell therapy in remission will not be considered a salvage regimen).
  2. Patients must be >/=18.
  3. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.
  4. Adequate hepatic (serum direct bilirubin </= 1.5 x upper limit normal (ULN) (or </= 3.0 x ULN if deemed to be elevated due to leukemia), alanine aminotransferase and/or aspartate transaminase </= 2.5 x ULN (or </= 5.0 x ULN if deemed elevated due to leukemia). Note: Subjects with documented Gilbert's Syndrome may have a total bilirubin > 1.5 × ULN. Potassium, magnesium, and calcium (normalized for albumin) levels should be within institutional normal limits)
  5. Adequate renal function as demonstrated by a calculated creatinine clearance >/= 50 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula (or MDRD formula)
  6. Patients must provide written informed consent.
  7. The interval from prior treatment to time of initiation of venetoclax and quizartinib administration will be at least 14 days or at least 5 half-lives (whichever is shorter) for cytotoxic/noncytotoxic agents. The half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator brochure's, or drug-administration manuals) and will be documented in the protocol eligibility document. The use of chemotherapeutic or anti-leukemic agents is not permitted during the study with the following exceptions: (1) intrathecal (IT) therapy for patients with controlled CNS leukemia at the discretion of the PI. Controlled CNS leukemia is defined by the absence of active clinical signs of CNS disease and no evidence of CNS leukemia on the most recent 2 simultaneous CSF evaluations.
  8. Continuation to Criteria No. 7: (2) Use of one dose of cytarabine (up to 2 g/m^2) or hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and on therapy. These medications will be recorded in the case-report form.
  9. Baseline ejection fraction by ECHO or MUGA must be >/= 50%.
  10. Females must be surgically (including have undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy); or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential (considered as following menarche and until becoming postmenopausal no menstrual period for a minimum of 12 months) , must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment.
  11. Women of childbearing potential must agree to use an adequate method of contraception during the study and until 90 days after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 90 days after the last treatment. Adequate methods of contraception include: Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  12. Continuation to Criteria No. 11: Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient Combination of any of the two following (a+b or a+c or b+c) a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository In case of use of oral contraception, women should have been stable on the same pill before taking study treatment. Note: Oral contraceptives are allowed but should be used in conjunction with a barrier method of contraception due to unknown effect of drug-drug interaction.
  13. Continuation to Criteria No. 12: Women are considered post-menopausal and not of child bearing potential if they have had 24 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation that was done at least 6 weeks prior to the planned start of protocol therapy. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
  Exclusion Criteria:
  1. Subject has t(8;21) or inv(16) karyotype abnormalities.
  2. Subject has acute promyelocytic leukemia (French-American-British Class M3 AML).
  3. Prior exposure to venetoclax or quizartinib at any time in the past.
  4. Patients with known allergy or hypersensitivity to quizartinib, venetoclax or any of their components.
  5. Patients with electrolyte abnormalities at study entry defined as follows: -Serum potassium < 3.5 mEq/L despite supplementation, or > 5.5 mEq/L. -Serum magnesium above or below the institutional normal limit despite adequate management. -Serum calcium (corrected for albumin levels) above or below institutional normal limit despite adequate management.
  6. Subject with a known history of being HIV positive (due to potential drug-drug interactions between antiretroviral medications and venetoclax, as well as anticipated venetoclax mechanism-based lymphopenia that may potentially increase the risk of opportunistic infections). Note: HIV testing is not required.
  7. Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.
  8. Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator and/or the PI would adversely affect his/her participating in this study. Patients who have had any major surgical procedure within 14 days of Day 1.
  9. Subject has a malabsorption syndrome or other condition that precludes enteral route of administration.
  10. Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to: a. Uncontrolled systemic infection requiring IV therapy (viral, bacterial or fungal). Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable. Patients with neutropenic fever considered infection related should be afebrile for at least 72 hours prior to first dose.
  11. Subject has a history of other malignancies prior to study entry, with the exception of: a. Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; b. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; c. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent. d. Patients on active antineoplastic or radiation therapy for a concurrent malignancy, with curative or palliative intent, at the time of screening. Maintenance therapy, hormonal therapy, or steroid therapy for well-controlled malignancy is allowed.
  12. Patients with a known positive hepatitis B or C infection by serology, with the exception of those with an undetectable viral load within 3 months (hepatitis B or C testing is not required prior to study entry). Subjects with serologic evidence of prior vaccination to HBV [i.e., HBs Ag-, and anti-HBs+] may participate.
  13. Female subjects who are pregnant or breastfeeding.
  14. Impaired cardiac function including any of the following: Screening ECG with a QTc >450 msec. The QTc interval will be calculated by Fridericia's correction factor (QTcF) at Screening and on Day 1 prior to the first dose of quizartinib. The QTcF will be derived from the average QTcF in triplicate. If QTcF >450 msec on Day 1, quizartinib will not be given. Patients with congenital long QT syndrome History or presence of sustained ventricular tachycardia requiring medical intervention Any history of clinically significant ventricular fibrillation or torsades de pointes. Known history of second or third degree heart block (may be eligible if the patient currently has a pacemaker). Sustained heart rate of <50/minute on screening or Day 1 ECG -Right bundle branch block + left anterior hemiblock (i.e. bifascicular block). Isolated RBBB will not be an exclusion criterion. Complete left bundle branch block
  15. Continuation to Criteria No. 14: Patients with myocardial infarction or unstable angina within 6 months prior to starting study drug -CHF NY Heart Association class III or IV. Atrial fibrillation documented within 2 weeks prior to first dose of study drug. Patients who are actively taking a moderate or strong CYP3A inhibitors medication. Moderate and strong CYP3A4 inhibitors should be stopped at least 3 days prior to the first dose of quizartinib and are prohibited at any time on study. Patients who are actively taking CYP3A inducers. CYP3A4 inducers should be stopped at least 3 days prior to the first dose of quizartinib and are prohibited at any time on study
  16. Continuation to Criteria No. 15: Patients who require treatment with concomitant drugs that prolong QT/QTc interval. QT/QTc prolonging drugs should be stopped at least 3 days prior to the first dose of quizartinib and are prohibited at any time on study. Known family history of congenital long QT syndrome

Relevance to patient case: not relevant