CPX-351 in Combination With Gemtuzumab Ozogamicin in Newly Diagnosed AML

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to determine the safety of combining the drugs gemtuzumab ozogamicin (GO) with CPX-351 in order to treat the disease, as well as to find the maximum tolerated dose level and recommended Phase 2 dose level of GO with a fixed dose of CPX-351.

Official Title
-----------------
A Phase 1/1b Dose Escalation and Expansion of CPX-351 in Combination With Gemtuzumab Ozogamicin in Newly Diagnosed Acute Myeloid Leukemia

Conditions
-----------------
Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: Vyxeos
* Drug: Gemtuzumab Ozogamicin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged ≥18 and ≤70 years with newly diagnosed any risk AML as defined by ELN 2017 criteria For females of child-bearing potential: use of highly effective contraception upon enrollment and during study participation and for an additional 6 months after the end of CPX-351 and Gemtuzumab ozogamicin administration: A female of child-bearing potential is considered when a sexually mature female: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months The effects of CPX-351 and gemtuzumab ozogamicin on the developing human fetus are unknown. For this reason, women of child-bearing potential as defined above must have a negative serum or urine pregnancy test within 24 hours prior to beginning study treatment. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner Myeloblasts expressing CD33 as determined by flow cytometry or immunohistochemistry ECOG ≤ 2 and eligible to receive intensive chemotherapy as determined by the treating physician Prior malignancy is allowed providing it does not require concurrent therapy. Exception: Active hormonal therapy is allowed. Prior hypomethylating agents (HMA) therapy including azacitidine or decitabine when used for non-AML diagnoses is allowed. Most recent dose must have been ≥14 days prior to day 1 of study treatment. Participants must have acceptable organ function Adequate cardiac function defined as ejection fraction of ≥50% as determined by multigated acquisition scan (MUGA) or 2D echocardiogram. Hydroxyurea is allowed for cytoreduction until day 1 of study treatment Exclusion Criteria: Prior treatment of AML except hydroxyurea and/or leukapheresis Participants with acute promyelocytic leukemia (APL). Known current and clinically active central nervous system (CNS) leukemia. Severe liver disease (cirrhosis, non-alcoholic steatohepatitis, sclerosing cholangitis) or patients with known Wilson's disease. Participants with known active infection with hepatitis B or hepatitis C virus Known allergic reactions to components of the CPX-351 (cytarabine or daunorubicin) or Gemtuzumab ozogamicin. Patients with any prior anthracycline exposure plus any planned on-study anthracycline exposure cannot not exceed 550 mg/m2 of daunorubicin (or equivalent). For participants who have received radiation therapy to the mediastinum, the total cumulative dose of anthracycline should not exceed 400 mg/m2 of daunorubicin(or equivalent). Hemodynamically unstable (subjects requiring vasopressor support will not be eligible). Treatment with another investigational drug within 14 days. Uncontrolled cardiac disease including congestive heart failure class III or IV by the NYHA, unstable angina (angina symptoms at rest), new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months. Any disorder that compromises the subject's ability to give written informed consent and/or to comply with study procedures. Any substance abuse, severe and/or uncontrolled medical, social or psychiatric conditions that may prevent the subject from completing the study, interfere with the evaluation of safety and/or efficacy, or interfere with the interpretation of the study results. Female subject who is pregnant or breastfeeding. Any patient with a known FLT3 ITD or FLT3 TKD mutation

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Dose escalation to determine the maximum tolerated dose (MTD) of CPX-351 in combination with Gemtuzumab Ozogamicin in participants with newly diagnosed acute myeloid leukemia. Participants will be treated in cohorts of size three to six and the dosage will be escalated if the clinical toxicity is acceptable. A total of 3 dose levels will be used. | Drug: Vyxeos<br>* Fixed dose of Vyxeos (44 mg/m2 daunorubicin and 100 mg/m2 cytarabine) (Day 1, 3, and 5) in combination with various dose schedules of Gemtuzumab Ozogamicin (GO)<br>* Other names: CPX-351;Drug: Gemtuzumab Ozogamicin<br>* Participants will be treated at the following dose levels: Dose Level 1 - Gemtuzumab Ozogamicin will administered 3mg/m2 on Day 1 Dose Level 2 - Gemtuzumab Ozogamicin will administered 3mg/m2 on Day 1 and 4 Dose Level 3 - Gemtuzumab Ozogamicin will administered 3mg/m2 on Day 1, 4, 7<br>* Other names: Mylotarg;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | Dose escalation will determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Vyxeos plus Gemtuzumab Ozogamicin. The MTD is the highest dose of the combination therapy that dose not cause unacceptable side effects. | Up to 18 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete Remission | Rate of complete remission (CR) and complete remission with incomplete blood count recovery (CRi). The definition of CR and CRi is based on the European LeukemiaNet 2017 Response Criteria for AML. | Up to 18 Months | 
| Measurable Residual Disease | Rate of measurable residual disease via RT-PCR for core binding factor leukemia as well as NPM1 mutated AML | Up to 18 Months | 
| Overall Survival | Overall survival is defined as the duration of time from start of treatment to the time of death from any cause or date of last contact. | Up to 5 years | 
| Relapse Free Survival (RFS) | RFS is defined as time interval between achievement of CR to time of relapse | Up to 18 Months |