NANT 2015-02: A Phase 1 Study of Lorlatinib (PF-06463922)

Phase 1 Study of Lorlatinib (PF-06463922), an Oral Small Molecule Inhibitor of ALK/ROS1, for Patients With ALK-Driven Relapsed or Refractory Neuroblastoma

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03107988

Enrollment

Registered

2017-04-11

Start date

2017-09-05

Completion date

2025-01-31

Last updated

2025-09-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neuroblastoma

Brief summary

Lorlatinib is a novel inhibitor across ALK variants, including those resistant to crizotinib. In this first pediatric phase 1 trial of lorlatinib, the drug will be utilized as a single agent and in combination with chemotherapy in patients with relapsed/refractory neuroblastoma. The dose escalation phase of this study (Cohort A1) uses a traditional Phase I 3+3 design. Once a recommended phase 2 pediatric dose is identified, an expansion cohort of 6 patients (Cohort B1), within which ALKi naïve patients will be prioritized, will be initiated. Parallel cohorts will be initiated in adults or patients with large BSA (Cohort A2) and in combination with chemotherapy upon establishing RP2D (Cohort B2).

Detailed description

Lorlatinib is a novel inhibitor across ALK variants, including those resistant to crizotinib. An adult phase 1 study established an RP2D of 100mg QD for lorlatinib. In this first pediatric phase 1 trial of lorlatinib, the drug will be utilized as a single agent and in combination with chemotherapy in patients with relapsed/refractory neuroblastoma. The dose escalation phase of this study (Cohort A1) uses a traditional Phase I 3+3 design. Once a recommended phase 2 pediatric dose is identified, an expansion cohort of 6 patients (Cohort B1), within which ALKi naïve patients will be prioritized, will be initiated. Parallel cohorts will be initiated in adults or patients with large BSA (Cohort A2) and in combination with chemotherapy upon establishing RP2D (Cohort B2). Lorlatinib will be administered orally via tablets or via oral dispersion if patient is unable to swallow tablets whole All patients will participate in mandatory pharmacokinetic testing.

Interventions

DRUGLorlatinib

Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.

DRUGCyclophosphamide

Cyclophosphamide 250mg/m2/day will be administered as a 30 minute IV infusion on days 1-5 of each cycle

DRUGTopotecan

Topotecan 0.75mg/m2/day will be administered as a 30 minute IV infusion immediately following cyclophosphamide on days 1-5 of each cycle

DRUGFilgrastim/pegfilgrastim

Filgrastim is to be given with each course beginning 24-48 hours following completion of cyclophosphamide and topotecan and continued through post-nadir count recovery with an ANC \> 2000/mm\^3 at 5mcg/kg/day. Filgrastim must be discontinued at least 24 hours prior to the start of the next course of therapy. Pegfilgrastim (100mcg/kg; 6mg maximum dose) may be substituted and is given one time at 24-48 hours from completion of cyclophosphamide and topotecan.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

1 Years to 99 Years

Healthy volunteers

Inclusion criteria

1\) Patients are required to have an activating ALK aberration in their tumor detected by certified assay (i.e. CLIA in the US.) prior to registration. The report from this test is required to be submitted for eligibility. Patients with at least one of the following genetic features in their tumor will be considered to have an activating ALK aberration: 1\. An ALK activating mutation; 2. ALK amplification (\> 10 signals of the ALK gene); 3. Presence of any ALK fusion protein that arises from a chromosomal translocation 2) Patients must have a diagnosis of neuroblastoma either by histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines. 3\) Patients must have a history of high-risk neuroblastoma according to COG risk classification at the time of study registration. Patients who were initially considered low or intermediate-risk, but then reclassified as high-risk are also eligible. 4\) All patients must have at least one of the following a) Recurrent/progressive disease: after the diagnosis of high risk neuroblastoma at any time prior to enrollment regardless of response to frontline therapy b) No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma b1) Refractory disease- a best overall response of no response/stable disease since diagnosis of high risk neuroblastoma and at least 4 cycles of induction therapy. No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma. b2) Persistent disease- a best overall response of no partial response since diagnosis of high risk neuroblastoma and at least 4 cycles of induction therapy. No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma. 5\) Patients must have at least ONE of the following (lesions may have received prior radiation therapy as long as they meet the other criteria listed below): 1. For recurrent/progressive or refractory disease, at least one MIBG avid bone site. 2. For persistent disease, if a patient has 3 or more MIBG avid lesions, then no biopsy is required. If a patients has only 1 or 2 MIBG avid bone lesion sites then biopsy confirmation of neuroblastoma or ganglioneuroblastoma in at least one MIBG avid site present at the time of enrollment is required to be obtained at any time point prior to enrollment. 3. For MIBG non-avid tumors, patients must have at least one FDG avid site and a biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment from at least one FDG-avid site. 6\) Any amount of neuroblastoma tumor cells in the bone marrow done at the time of study enrollment based on routine morphology with or without immunocytochemistry in at least one sample from bilateral aspirates and biopsies. 7\) At least one soft tissue lesion that meets criteria for a TARGET lesion as defined by:  1. SIZE: Lesion can be accurately measured in at least one dimension with a longest diameter ≥ 10 mm, or for lymph nodes ≥ 15 mm on short axis. Lesions meeting size criteria will be considered measurable. 2. In addition to size, a lesion needs to meet one of the following criteria except for patients with parenchymal CNS lesions which only need to meet size criteria: b1) MIBG avid. For patients with recurrent/progressive or refractory disease, no biopsy is required. For patients with persistent disease only: If a patient has only 1 or 2 MIBG avid lesions sites, then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site present at time of enrollment is required to be obtained. If a patient has 3 or more MIBG avid lesions, then no biopsy is required. b2) MIBG non avid tumors: Patients must have at least one FDG avid site and biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one FDG-PET avid site present at the time of enrollment. 8\) At least one non-target soft tissue lesion that is not measurable, but had a biopsy positive for neuroblastoma and/or ganglioneuroblastoma or is MIBG avid at any time prior to enrollment. 9\) Patients must have a life expectancy of at least 12 weeks and a Lansky (≤16 years) or Karnofsky (\>16 years) score of at least 50. 10\) Prior Therapy 1. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study registration. 2. Patients must not have received the therapies indicated below after disease evaluation or within the specified time period prior to registration on this study as follows: 1\. Myelosuppressive chemotherapy: must not have received within 2 weeks prior to registration. 2\. Biologic anti-neoplastics- agents not known to be associated with reduced platelet or ANC counts (including retinoids): must not have received within 7 days prior to registration. 3\. Monoclonal antibodies: must have received last dose at least 7 days or 3 half-lives whichever is longer, but no longer than 30 days (with recovery of any associated toxicities), prior to protocol therapy. 4\. Cellular Therapy (e.g. modified T cells, NK cells, dentritic cells etc.): must not have received within 3 weeks and resolution of all toxicities. 5\. Radiation: must not have received small port radiation within 7 days prior to registration. 6\. Hematopoietic Stem Cell Transplant: 7. IVIG 11) All patients must have adequate organ function defined as: \- Hematological Function: 1\. Absolute Phagocyte count (APC= neutrophils and monocytes): ≥ 1000/µL 2\. Absolute Neutrophil count: ≥750/µL 3\. Absolute Lymphocyte count ≥ 500/µL 4\. Platelet count: ≥ 50,000/µL (A1, A2, and B1); ≥ 75,000/µL (B2), transfusion independent (no platelet transfusions within 1 week) 5\. Hemoglobin ≥ 10 g/dL (may transfuse) 6\. Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria above. \- Renal Function: Age-adjusted serum creatinine ≤ to 1.5 x normal for age/gender OR creatinine clearance or GFR greater than or equal to 60 cc/min/1.73m2 \- Liver Function: Total bilirubin ≤ 1.5 x normal for age, AND SGPT (ALT) 135 and SGOT (AST) ≤ 3 x upper limit of normal. Sinusoidal obstruction syndrome (SOS) if present, must be stable or improving clinically \- Cardiac Function: Normal ejection fraction documented by either echocardiogram or radionuclide MUGA evaluation OR Normal fractional shortening documented by echocardiogram \- Pulmonary Function: No dyspnea at rest, no oxygen requirement. * Neuropsychological Function: Patients must exhibit ≤ grade 1 as defined by CTCAE V4 of nervous system disorders and psychiatric disorders 12) Reproductive Status: All post-menarchal females must have a negative beta-HCG. Males and females of reproductive age and childbearing potential must use effective contraception for the duration of their participation. 13\) Patients with other ongoing serious medical issues must be approved by the study chair prior to registration. 14\) Prior ALK inhibitor treatment- patients must not have been previously treated with lorlatinib. Prior therapy with other ALK inhibitors is allowed. 15\) Concomitant Therapy Restrictions: 1. Patients may not receive any other anti-cancer agents or radiotherapy while on protocol therapy. 2. Patient must not be receiving chronic systemic corticosteroids at doses greater than physiologic dosing (inhaled corticosteroids acceptable) 3. CYP34A inhibitors 4. CYP34A inducers 5. CYP34A substrates

Exclusion criteria

\- Pregnancy, breast feeding, or unwillingness to use effective contraception during the study. * Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study. * Patients with disease of any major organ system that would compromise their ability to withstand therapy. * Patients who have received prior allogeneic stem cell transplant * Patients who are on hemodialysis. * Patients with an active or uncontrolled infection. * Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C. * Patient with known history of acute or chronic severe psychiatric disorders * Patient with current history of suicidal ideation and history of suicide attempt in their lifetime * Patient declines participation in NANT 2004-05, the NANT Biology Study

Design outcomes

Primary

Measure	Time frame	Description
Describe Hematological Toxicities (B2)	All toxicities from enrollment through 30 days following end of protocol therapy, an average of 10 months	Proportion of patients with any grade 3 or greater hematological toxicities in B2
Describe Non-Hematological Toxicities (A2)	All toxicities from enrollment through 30 days following end of protocol therapy, an average of 10 months	Proportion of patients with any grade 3 or greater non-hematological toxicities in A2
MTD/RP2D Determination A1	All toxicities from enrollment until completion of course 2 (Day 56)	Proportion of patients with course 1 DLT and/or course 2 neuropsychological DLT in cohort A1
MTD/RP2D Determination A2	All toxicities from enrollment until completion of course 2 (Day 56)	Proportion of patients with course 1 DLT and/or course 2 neuropsychological DLT in cohort A2
MTD/RP2D Determination B2	All toxicities from enrollment until completion of course 1 (Day 28)	Proportion of patients with course 1 DLT in cohort B2
Describe Non-Hematological Toxicities (A1 and B1)	All toxicities from enrollment through 30 days following end of protocol therapy, an average of 10 months	Proportion of patients with any grade 3 or greater non-hematological toxicities on any course in A1 and B1
Describe Hematological Toxicities (A1 and B1)	All toxicities from enrollment through 30 days following end of protocol therapy, an average of 10 months	Proportion of patients with any grade 3 or greater hematological toxicities on any course in A1 and B1
Describe Hematological Toxicities (A2)	All toxicities from enrollment through 30 days following end of protocol therapy, an average of 10 months	Proportion of patients with any grade 3 or greater hematological toxicities in A2
Describe Non-Hematological Toxicities (B2)	All toxicities from enrollment through 30 days following end of protocol therapy, an average of 10 months	Proportion of patients with any grade 3 or greater non-hematological toxicities in B2

Secondary

Measure	Time frame	Description
Pharmacokinetics A1 and B1-Steady State AUC	Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)	Steady State AUC for lorlatinib in patients in cohort A1 and B1
Pharmacokinetics A2-Steady State AUC	Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)	Steady State AUC for lorlatinib in patients in cohort A2
Pharmacokinetics B2-Steady State AUC	Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)	Steady State AUC for lorlatinib in patients in cohort B2
Overall Response A1 and B1	From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months	Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort A1 and B1
Overall Response A2	From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months	Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort A2
Overall Response B2	From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months	Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort B2
Pharmacokinetics A1 and B1-Cmax	Day 15	Cmax for lorlatinib in patients in cohort A1 and B1
Pharmacokinetics A2-Cmax	Day 15	Cmax for lorlatinib in patients in cohort A2
Pharmacokinetics B2-Cmax	Day 15	Cmax for lorlatinib in patients in cohort B2

Countries

Canada, France, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Cohort A1 DL1 Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 45 mg/m2/dose. Patients must be under 18 years of age at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.	3
Cohort A1 DL2 Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 60 mg/m2/dose. Patients must be under 18 years of age at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.	3
Cohort A1 DL3 Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 75 mg/m2/dose. Patients must be under 18 years of age at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.	3
Cohort A1 DL4 Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 95 mg/m2/dose. Patients must be under 18 years of age at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.	10
Cohort A1 DL5 Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 115 mg/m2/dose. Patients must be under 18 years of age at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.	6
Cohort A2 DL 3A Lorlatinib will be given at 100 mg orally once daily continuously for 28 days. Patients must be 18 years of age or older at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.	6
Cohort A2 DL4A Lorlatinib will be given at 150 mg orally once daily continuously for 28 days. Patients must be 18 years of age or older at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.	6
Cohort A2 DL4A Expansion Lorlatinib will be given at 150 mg orally once daily continuously for 28 days. Patients must be 18 years of age or older at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.	4
Cohort B1 DL5 Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 115 mg/m2/dose. Patients must be under 18 years of age at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.	5
Cohort B2 DL4B Lorlatinib will be given orally once daily continuously for 28 days at 95mg/m2/dose. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be under 18 years of age at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets. Cyclophosphamide: Cyclophosphamide 250mg/m2/day will be administered as a 30 minute IV infusion on days 1-5 of each cycle Topotecan: Topotecan 0.75mg/m2/day will be administered as a 30 minute IV infusion immediately following cyclophosphamide on days 1-5 of each cycle Filgrastim/pegfilgrastim: Filgrastim is to be given with each course beginning 24-48 hours following completion of cyclophosphamide and topotecan and continued through post-nadir count recovery with an ANC \> 2000/mm\^3 at 5mcg/kg/day. Filgrastim must be discontinued at least 24 hours prior to the start of the next course of therapy. Pegfilgrastim (100mcg/kg; 6mg maximum dose) may be substituted and is given one time at 24-48 hours from completion of cyclophosphamide and topotecan.	3
Cohort B2 DL5B Lorlatinib will be given orally once daily continuously for 28 days at 115mg/m2/dose. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be under 18 years of age at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets. Cyclophosphamide: Cyclophosphamide 250mg/m2/day will be administered as a 30 minute IV infusion on days 1-5 of each cycle Topotecan: Topotecan 0.75mg/m2/day will be administered as a 30 minute IV infusion immediately following cyclophosphamide on days 1-5 of each cycle Filgrastim/pegfilgrastim: Filgrastim is to be given with each course beginning 24-48 hours following completion of cyclophosphamide and topotecan and continued through post-nadir count recovery with an ANC \> 2000/mm\^3 at 5mcg/kg/day. Filgrastim must be discontinued at least 24 hours prior to the start of the next course of therapy. Pegfilgrastim (100mcg/kg; 6mg maximum dose) may be substituted and is given one time at 24-48 hours from completion of cyclophosphamide and topotecan.	13
Cohort B2 DL3A Lorlatinib will be given orally once daily continuously for 28 days at 100mg/day. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be 18 years of age or older at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets. Cyclophosphamide: Cyclophosphamide 250mg/m2/day will be administered as a 30 minute IV infusion on days 1-5 of each cycle Topotecan: Topotecan 0.75mg/m2/day will be administered as a 30 minute IV infusion immediately following cyclophosphamide on days 1-5 of each cycle Filgrastim/pegfilgrastim: Filgrastim is to be given with each course beginning 24-48 hours following completion of cyclophosphamide and topotecan and continued through post-nadir count recovery with an ANC \> 2000/mm\^3 at 5mcg/kg/day. Filgrastim must be discontinued at least 24 hours prior to the start of the next course of therapy. Pegfilgrastim (100mcg/kg; 6mg maximum dose) may be substituted and is given one time at 24-48 hours from completion of cyclophosphamide and topotecan.	1
Cohort B2 DL4A Lorlatinib will be given orally once daily continuously for 28 days at 150mg/day. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be 18 years of age or older at time of enrollment. Lorlatinib: Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets. Cyclophosphamide: Cyclophosphamide 250mg/m2/day will be administered as a 30 minute IV infusion on days 1-5 of each cycle Topotecan: Topotecan 0.75mg/m2/day will be administered as a 30 minute IV infusion immediately following cyclophosphamide on days 1-5 of each cycle Filgrastim/pegfilgrastim: Filgrastim is to be given with each course beginning 24-48 hours following completion of cyclophosphamide and topotecan and continued through post-nadir count recovery with an ANC \> 2000/mm\^3 at 5mcg/kg/day. Filgrastim must be discontinued at least 24 hours prior to the start of the next course of therapy. Pegfilgrastim (100mcg/kg; 6mg maximum dose) may be substituted and is given one time at 24-48 hours from completion of cyclophosphamide and topotecan.	1
Total	64

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG007	FG008	FG009	FG010
Overall Study	Adverse Event	0	0	0	1	0	1	1	0	0	0
Overall Study	Disease Progression or Relapse	1	2	2	5	1	1	0	0	1	4
Overall Study	Ineligible	0	0	0	0	0	0	0	1	0	0

Baseline characteristics

Characteristic	Total	Cohort A1 DL2	Cohort A1 DL3	Cohort A1 DL1	Cohort A1 DL4	Cohort A1 DL5	Cohort A2 DL 3A	Cohort A2 DL4A	Cohort A2 DL4A Expansion	Cohort B1 DL5	Cohort B2 DL4B	Cohort B2 DL5B	Cohort B2 DL3A	Cohort B2 DL4A
Age, Categorical <=18 years	48 Participants	3 Participants	3 Participants	3 Participants	10 Participants	6 Participants	0 Participants	2 Participants	0 Participants	5 Participants	3 Participants	13 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	16 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	6 Participants	4 Participants	4 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	56 Participants	2 Participants	2 Participants	3 Participants	9 Participants	6 Participants	5 Participants	6 Participants	2 Participants	5 Participants	3 Participants	11 Participants	1 Participants	1 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	2 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	4 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	3 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	5 Participants	0 Participants	0 Participants	0 Participants	2 Participants	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	10 Participants	1 Participants	0 Participants	0 Participants	0 Participants	3 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants	4 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	45 Participants	2 Participants	2 Participants	3 Participants	8 Participants	3 Participants	5 Participants	6 Participants	3 Participants	1 Participants	2 Participants	8 Participants	1 Participants	1 Participants
Sex: Female, Male Female	35 Participants	2 Participants	0 Participants	2 Participants	6 Participants	3 Participants	4 Participants	3 Participants	3 Participants	2 Participants	1 Participants	7 Participants	1 Participants	1 Participants
Sex: Female, Male Male	29 Participants	1 Participants	3 Participants	1 Participants	4 Participants	3 Participants	2 Participants	3 Participants	1 Participants	3 Participants	2 Participants	6 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk	EG011 affected / at risk	EG012 affected / at risk
deaths Total, all-cause mortality	2 / 3	3 / 3	2 / 3	9 / 10	3 / 6	4 / 6	2 / 6	0 / 4	3 / 5	2 / 3	7 / 13	0 / 1	0 / 1
other Total, other adverse events	3 / 3	3 / 3	3 / 3	9 / 10	6 / 6	6 / 6	6 / 6	4 / 4	5 / 5	3 / 3	12 / 13	1 / 1	1 / 1
serious Total, serious adverse events	1 / 3	1 / 3	0 / 3	3 / 10	2 / 6	4 / 6	3 / 6	1 / 4	3 / 5	3 / 3	10 / 13	1 / 1	1 / 1

Outcome results

Primary

Describe Hematological Toxicities (A1 and B1)

Proportion of patients with any grade 3 or greater hematological toxicities on any course in A1 and B1