Acute Myeloid Leukemia, AML
Conditions
Brief summary
The purpose of this study is to evaluate the safety and tolerability of Palbociclib in combination with investigational (experimental) drug, CPX-351 and evaluate the efficacy of Palbociclib in combination with chemotherapy as measured by overall response rate (ORR), i.e. complete response (CR) and CR with incomplete blood count recovery (CRi) by 2003 IWG criteria.
Detailed description
The objectives of this study are to evaluate the safety and tolerability of Palbociclibin combination with CPX-351, and to evaluate the efficacy of Palbociclibin combination with chemotherapy as measured by overall response rate (ORR), i.e. complete response (CR) and CR with incomplete blood count recovery (CRi) by IWG criteria. CPX-351 is an investigational drug that works as formulation of a fixed combination of the antineoplastic (acting to prevent, inhibit or halt the development of a neoplasm (a tumor)) drugs cytarabine and daunorubicin. Palbociclibis an investigational drug that works to induce early G1 arrest by inhibiting CDK4/6, which are two types of CDKs that are overexpressed in AML cell cancer lines. CPX-351 and Palbociclib is experimental because it is not approved by the Food and Drug Administration (FDA). This is a single arm, open label study of the combination of Palbociclib with CPX-351 in adults with AML. The trial consists of two components: phase I to evaluate the safety with dose escalation of Palbociclib in combination with CPX-351 and phase II to evaluate the overall response rate of the combination in the targeted participant population.
Interventions
DRUGPalcociclib
Palbociclib is an investigational (experimental) drug that works to induce early G1 arrest by inhibiting CDK4/6, which are two types of CDKs that are overexpressed in AML cell cancer lines. Palbociclib is experimental because it is not approved by the Food and Drug Administration (FDA). Palbociclib will be supplied as capsules or tablets containing 125 mg equivalents of Palbociclib free base
DRUGCPX-351
CPX-351 (daunorubicin and cytarabine) liposome for injection is a combination of daunorubicin and cytarabine in a 1:5 molar ratio encapsulated in liposomes for intravenous administration. CPX-351 is an investigational (experimental) drug that works as formulation of a fixed combination of the antineoplastic drugs cytarabine and daunorubicin. CPX-351 is experimental because it is not approved by the Food and Drug Administration (FDA).
Sponsors
Sudipto Mukherjee, MD, PhD, MPH
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single arm, open label study of the combination of Palbociclib with CPX-351 in adults with AML. The trial consists of two components: phase I to evaluate the safety with dose escalation of Palbociclib in combination with CPX-351 and phase II to evaluate the overall response rate of the combination in the targeted patient population. A cycle is 28 days.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Newly diagnosed acute myeloid leukemia according to 2016 WHO criteria(excluding APL \[AML-M3\]). * Eastern Cooperative Oncology Group (ECOG) Performance Status \<2 * Subjects must have normal organ function as defined below: * Total bilirubin \<2 times upper limit of normal ((≤ 3 x ULN if considered to be due to leukemic involvement or Gilbert's syndrome) or if higher than 2 times upper limit of normal with approval from the PI * Serum Creatinine \<2 x ULNor if higher than 2 times upper limit of normal with approval from the PI * Left ventricular ejection fraction of ≥45% * Patients with secondary AML arising out of MDS (all subtypes under WHO classification), chronic myelomonocytic leukemia (CMML) and therapy-related AML are eligible. * Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment. All men and women of childbearing potential must use acceptable methods of birth control throughout the study * Subjects must have the ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Prior treatment with CPX-351, Palbociclib or other cell cycle inhibitors. * Any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent. * Any active malignancy (unrelated, non-hematological malignancy) diagnosed within the past 6 months of starting the study drug (other than curatively treated carcinoma-in-situ of the cervix or non-melanoma skin cancer). * History of allergic reactions attributed to compounds of similar chemical or biologic composition to CPX-351, Palbociclib or other cell cycle inhibitors. * Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Known history of HIV or active hepatitis B or C. * No major surgery within 2 weeks prior to study enrollment. * Pregnancy or breast feeding * Male and female patients who are fertile who do not agree to use an effective barrier methods of birth control (i.e. abstinence) to avoid pregnancy while receiving study treatment. * Acute promyelocytic leukemia (APL)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Experimental Dose of Palbociclibin Combination With CPX-351 as Measured by Number of Participants With Dose Limiting Toxicities. | Between days 28-35 of starting treatment | If Grade 3-4 non-hematologic toxicity is observed in 1 or less of 6 patients treated, the dose of the study drug will be considered safe/tolerable. If Grade 3-4 non-hematologic toxicity is observed in 2 or more of 6 patients treated, 6 additional patients will be treated on the Phase IIa portion at a lower dose level (100 mg po). |
| Efficacy of Palbociclibin Combination With Chemotherapy as Measured by Overall Response Rate (ORR). | Up to 2 years from end of treatment, up to 27 months | Efficacy of Palbociclibin combination with chemotherapy as measured by overall response rate (ORR) which is defined as complete response (CR) and CR with incomplete blood count recovery (CRi) by IWG criteria. Complete remission is defined as: Bone marrow blasts \<5%; absence ofcirculating blasts and blasts with Auerrods; absence of extramedullarydisease; absolute neutrophil count \>1.0x 109/L (1,000/μL); platelet count \>100 x109/L (100,000/μL) and CR with incomplete blood count recovery is defined as: All CR criteria except for residualneutropenia \[\<1.0 x 109/L (1,000/μL)\] orthrombocytopenia \[\<100 x 109/L(100,000/μL)\]. Either of these responses will constitute ORR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Response (TTR) | Up to 2 years from end of treatment | TTR is defined as the time it takes from the start date of the treatment to the date of achievement of response (as per the definition of response mentioned in the 2003 IWG criteria). |
| Duration of Response (DOR) | Up to 2 years from end of treatment | DOR is measured between the date of response to date of loss of response. |
| Event-free Survival (EFS) | Up to 2 years from end of treatment | EFS measured from the date of entry into a study to the date of primary refractory disease, or relapse from CR, or CRi, or death from any cause; patients not known to have any of these events are censored on the date they were last examined |
| Overall Survival (OS) Probability | Up to 2 years from end of treatment, up to 27 months | OS probability measured from the date of entry into a clinical trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I Palbociclib will be given at dose level 1 (75 mg po) on day -1 and -2, day 0 will be rest and then CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) will be started on day 1, 3, and 5 along with Palbociclib on day 2, 4, and 6 followed by rest/monitoring period (days 7-35) | 9 |
| Phase II Patients will receive 1-2 induction courses of the combination of Palbociclib and CPX-351. | 26 |
| Total | 35 |
Baseline characteristics
| Characteristic | Phase II | Total | Phase I |
|---|---|---|---|
| Age, Customized | 56 years | 56 years | 47 years |
| AML(Acute Myeloid Leukemia) Classification AML not otherwise specified | 16 Participants | 19 Participants | 3 Participants |
| AML(Acute Myeloid Leukemia) Classification AML with certain genetic abnormalities | 8 Participants | 10 Participants | 2 Participants |
| AML(Acute Myeloid Leukemia) Classification AML with myelodysplasia-related changes | 2 Participants | 4 Participants | 2 Participants |
| AML(Acute Myeloid Leukemia) Classification Unknown | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 33 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| History of Cancer AML | 22 Participants | 24 Participants | 2 Participants |
| History of Cancer MDS | 1 Participants | 1 Participants | 0 Participants |
| History of Cancer MPN | 0 Participants | 1 Participants | 1 Participants |
| History of Cancer No cancer | 3 Participants | 8 Participants | 5 Participants |
| History of Cancer Other cancer | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 22 Participants | 29 Participants | 7 Participants |
| Sex: Female, Male Female | 14 Participants | 18 Participants | 4 Participants |
| Sex: Female, Male Male | 12 Participants | 17 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 9 | 0 / 26 |
| other Total, other adverse events | 9 / 9 | 26 / 26 |
| serious Total, serious adverse events | 1 / 9 | 3 / 26 |
Outcome results
Primary
Efficacy of Palbociclibin Combination With Chemotherapy as Measured by Overall Response Rate (ORR).
Efficacy of Palbociclibin combination with chemotherapy as measured by overall response rate (ORR) which is defined as complete response (CR) and CR with incomplete blood count recovery (CRi) by IWG criteria. Complete remission is defined as: Bone marrow blasts \<5%; absence ofcirculating blasts and blasts with Auerrods; absence of extramedullarydisease; absolute neutrophil count \>1.0x 109/L (1,000/μL); platelet count \>100 x109/L (100,000/μL) and CR with incomplete blood count recovery is defined as: All CR criteria except for residualneutropenia \[\<1.0 x 109/L (1,000/μL)\] orthrombocytopenia \[\<100 x 109/L(100,000/μL)\]. Either of these responses will constitute ORR.
Time frame: Up to 2 years from end of treatment, up to 27 months
Population: ORR was measured only for Phase II
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase II | Efficacy of Palbociclibin Combination With Chemotherapy as Measured by Overall Response Rate (ORR). | 22 Participants |
Primary
Safety and Tolerability of Experimental Dose of Palbociclibin Combination With CPX-351 as Measured by Number of Participants With Dose Limiting Toxicities.
If Grade 3-4 non-hematologic toxicity is observed in 1 or less of 6 patients treated, the dose of the study drug will be considered safe/tolerable. If Grade 3-4 non-hematologic toxicity is observed in 2 or more of 6 patients treated, 6 additional patients will be treated on the Phase IIa portion at a lower dose level (100 mg po).
Time frame: Between days 28-35 of starting treatment
Population: Safety and tolerability only measured for Phase I
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I | Safety and Tolerability of Experimental Dose of Palbociclibin Combination With CPX-351 as Measured by Number of Participants With Dose Limiting Toxicities. | 0 Participants |
Secondary
Duration of Response (DOR)
DOR is measured between the date of response to date of loss of response.
Time frame: Up to 2 years from end of treatment
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Phase I | Duration of Response (DOR) | 302.91 Days |
| Phase II | Duration of Response (DOR) | 523.7 Days |
Secondary
Event-free Survival (EFS)
EFS measured from the date of entry into a study to the date of primary refractory disease, or relapse from CR, or CRi, or death from any cause; patients not known to have any of these events are censored on the date they were last examined
Time frame: Up to 2 years from end of treatment
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Phase I | Event-free Survival (EFS) | 188.23 Days |
| Phase II | Event-free Survival (EFS) | 406.09 Days |
Secondary
Overall Survival (OS) Probability
OS probability measured from the date of entry into a clinical trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive
Time frame: Up to 2 years from end of treatment, up to 27 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Overall Survival (OS) Probability | 25 percentage of paticipants |
| Phase II | Overall Survival (OS) Probability | 76 percentage of paticipants |
Secondary
Time to Response (TTR)
TTR is defined as the time it takes from the start date of the treatment to the date of achievement of response (as per the definition of response mentioned in the 2003 IWG criteria).
Time frame: Up to 2 years from end of treatment
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Phase I | Time to Response (TTR) | 43.37 Days |
| Phase II | Time to Response (TTR) | 41.27 Days |