Anaplastic Astrocytoma, Anaplastic Oligoastrocytoma, Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, H3 K27M-Mutant, Glioblastoma, Gliosarcoma
Conditions
Brief summary
This phase I trial studies the side effects and the best dose of adavosertib when given together with local radiation therapy in treating children with newly diagnosed diffuse intrinsic pontine gliomas. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays, gamma rays, neutrons, protons, or other sources to kill tumor cells and shrink tumors. Giving adavosertib with local radiation therapy may work better than local radiation therapy alone in treating diffuse intrinsic pontine gliomas.
Detailed description
PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) or recommended phase 2 dose and schedule of the adavosertib (Wee1 inhibitor AZD1775 \[MK-1775\]) administered concurrently with radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). II. To define and describe the toxicities of AZD1775 (MK-1775) given concurrently with radiation therapy in children with newly diagnosed DIPG. III. To characterize the pharmacokinetics of AZD1775 (MK-1775) in children with newly diagnosed DIPG when given concurrently with radiation therapy. SECONDARY OBJECTIVES: I. To preliminarily define the antitumor activity of AZD1775 (MK-1775) within the confines of a phase 1 study, including response rate, progression free survival, and overall survival of treated patients. II. To assess the biologic activity of AZD1775 (MK-1775) by measuring expression of phosphorylated-cell division cycle 2 G1 to S and G2 to M (p-CDC2) (cyclin-dependent kinase 1 \[CDK1\]) and phosphorylated-histone H3 (p-HH3) in peripheral blood mononuclear cells (PBMCs) before and after administration of AZD1775 (MK-1775) in children with newly diagnosed DIPG. III. To assess the biologic activity of AZD1775 (MK-1775) by measuring expression of gamma-H2A histone family, member X (H2AX) in PBMCs, a marker of deoxyribonucleic acid (DNA) double-strand breaks (dsDNA), before and after administration of AZD1775 (MK-1775) in children with newly diagnosed DIPG. OUTLINE: This is a dose-escalation study of adavosertib. Patients undergo radiation therapy 5 days a week for 6 weeks (up to 30 fractions). Patients also receive adavosertib orally (PO) on days 1-5 of weeks 1, 3, and 5; days 1-5 of weeks 1, 3, and 5 AND days 1, 3, and 5 of weeks 2, 4, and 6; OR days 1-5 of weeks 1-6 depending on dose level assignment. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 2 months for 6 months, and then every 3 months thereafter.
Interventions
DRUGAdavosertib
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
RADIATIONRadiation Therapy
Undergo radiation therapy
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
37 Months to 21 Years
Healthy volunteers
No
Inclusion criteria
* Patients with newly diagnosed DIPGs, defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible without histologic confirmation * Patients with brainstem tumors that do not meet these criteria or are not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma, gliosarcoma, diffuse midline glioma with histone H3 K27M mutation, or anaplastic mixed glioma; patients with pilocytic astrocytoma, fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not eligible * Patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician * Enrollment must be no later than 28 days after the date of radiographic diagnosis or surgery, whichever is the later date * Patients must have a body surface area \>= 0.35 m\^2 at the time of study enrollment * Karnofsky \>= 50% for patients \> 16 years of age and Lansky \>= 50 for patients =\< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score * Patients must not have received any prior anti-cancer therapy such as chemotherapy, radiation therapy, immunotherapy or bone marrow transplant for the treatment of DIPG; prior dexamethasone and/or surgery are allowed * Peripheral absolute neutrophil count (ANC) \>= 1000/mm\^3 * Platelet count \>= 100,000/mm\^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) * Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or * A serum creatinine based on age/gender as follows: * 0.8 mg/dL (3 to \< 6 years of age) * 1.0 mg/dL (6 to \< 10 years of age) * 1.2 mg/dL (10 to \< 13 years of age) * 1.5 mg/dL (male) or 1.4 mg/dl (female) (13 to \< 16 years of age) * 1.7 mg/dL (male) or 1.4 mg/dl (female) (\>= 16 years of age) * Bilirubin (sum of conjugated + unconjugated) =\< 1.5 x upper limit of normal (ULN) for age * Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 3 x ULN = 135 units per liter (U/L); for the purpose of this study, the ULN for SGPT is 45 U/L * Serum glutamic oxaloacetic transaminase (SGOT) aspartate aminotransferase \[AST\] =\< 3 x ULN = 150 U/L; for the purpose of this study, the ULN for SGOT is 50 U/L * Serum albumin \>= 2 g/dL * Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled * Nervous system disorders (Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]5) resulting from prior therapy must be =\< grade 2 with the exception of tendon reflex (deep tendon reflex \[DTR\]); any grade of DTR is eligible * Corrected QT interval (QTc) =\< 480 msec * All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
Exclusion criteria
* Pregnant or breast-feeding women may not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; negative serum or urine pregnancy test within 3 days prior to enrollment * Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive methods as follows: fertile females of childbearing potential who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation; male patients willing to abstain or use barrier contraception (i.e. condoms) for the duration of the study and for 3 months after treatment stops * Patients receiving corticosteroids are eligible for this trial * Patients who are currently receiving another investigational drug are not eligible * Patients who are currently receiving other anti-cancer agents are not eligible * Patients must not currently be receiving enzyme inducing anticonvulsants * Patients should avoid concomitant medication known or suspected to prolong QTc interval or cause Torsades De Pointes; if possible, alternative agents should be considered; patients who are receiving drugs that prolong the QTc are eligible if the drug is necessary and no alternatives are available * Patients who are currently receiving drugs that are strong or moderate inhibitors and/or inducers of CYP3A4, sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow therapeutic range are not eligible; the use of aprepitant or fosaprepitant as an antiemetic is prohibited due to early drug interaction data demonstrating increased exposure to AZD1775; the use of hydroxymethylglutary (HMG) coenzyme-A (Co-A) inhibitors such as atorvastatin is prohibited * Herbal preparations are not allowed throughout the study; these herbal medications include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng; patients should stop using these herbal medications 7 days prior to study enrollment * Any known hypersensitivity or contraindication to the components of the study drug AZD1775 * Patients must not receive metformin for at least 5 days prior to enrollment and for the duration of study treatment * Patients must be able to swallow capsules; nasogastric or gastrostomy feeding (G) tube administration is not allowed * Patients who have an uncontrolled infection are not eligible * Patients who have received a prior solid organ transplantation are not eligible * Patients with cardiac diseases ongoing or in the past 6 months (e.g. congestive heart failure, acute myocardial infarction, significant uncontrolled arrhythmias) are not eligible for this trial * Major surgical procedures =\< 28 days of beginning study treatment, or minor surgical procedures (including ventriculoperitoneal \[VP\] shunt placement or stereotactic biopsy of the tumor) =\< 7 days; no waiting period required following port-a-cath or other central venous access placement * Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose of Adavosertib | Up to 42 days | MTD will be defined as the maximum dose at which fewer than one-third of patients experience a dose-limiting toxicity graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. |
| Number of Dose Limiting Toxicity With Adavosertib | Up to 42 days | Number of patients with dose limiting toxicity stratified by dose level and the toxicity will be graded using the NCI CTCAE version 4.0. |
| Area Under the Time Concentration Curve of Adavosertib | up to 24 hours | Median (min, max) of the area under the concentration time curve adavosertib assessed at 1, 2, 4, 6, 8, and 24 hours post dose on day 1 stratified by dose level and study part. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in p-CDC2 of Adavosertib | Baseline to day 8 | Median (min, max) change in expression of p-CDC2 in peripheral blood mononuclear cells (PBMCs) before and after administration by dose level and study part. |
| Number of Patients With Response to Adavosertib | Up to 4 years | Number of participants with response (CR/PR) by maximal 2-dimensional measures with CR: disappearance of all abnormal signal within the brainstem; PR: at least 50% decrease in the sum o the products of the two perpendicular diameters of the target lesion. |
| Change in Expression of ɤ(Gamma)-H2AX of Adavosertib | Baseline to day 8 | Median (min, max) relative change in expression of gamma-H2AX of adavosertib by dose level and study part. |
| Change in Expression of p-HH3 of Adavosertib | Baseline to day 8 | Median (min, max) change in expression of p-HH3 in peripheral blood mononuclear cells (PBMCs) before and after administration by dose level and study part |
| Progression-free Survival (PFS) of Adavosertib | Up to 4 years | Median (95% CI) time to progression or death stratified by dose level and study part. PFS was defined as time from start date of the first treatment to the date of disease progression or death due to any causes which ever occurred first. |
| Overall Survival (OS) of Adavosertib | Up to 4 years | Median (95% CI) time to progression or death stratified by dose level and study part. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1: 50 mg/m^2 Patients receive 50 mg/m\^2 adavosertib daily (Monday- Friday), alternating weeks. | 6 |
| Dose Level 2: 50 mg/m^2 Patients receive 50 mg/m\^2 adavosertib daily (Monday-Friday), alternating with weeks of QOD dosing. | 6 |
| Dose Level 3: 50 mg/m^2 Patients receive 50 mg/m\^2 adavosertib daily (Monday- Friday), during weeks 1-6 | 7 |
| Dose Level 4: 95 mg/m^2 Patients receive 95 mg/m\^2 adavosertib daily (Monday- Friday), during weeks 1-6 | 7 |
| Dose Level 5: 130 mg/m^2 Patients receive 130 mg/m\^2 adavosertib daily (Monday- Friday), during weeks 1-6 | 7 |
| Dose Level 6: 160 mg/m^2 Patients receive 160 mg/m\^2 adavosertib daily (Monday- Friday), during weeks 1-6 | 6 |
| Dose Level 7: 200 mg/m^2 Patients receive 200 mg/m\^2 adavosertib daily (Monday- Friday), during weeks 1-6 | 7 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Dose Level 1: 50 mg/m^2 | Dose Level 2: 50 mg/m^2 | Dose Level 3: 50 mg/m^2 | Dose Level 4: 95 mg/m^2 | Dose Level 5: 130 mg/m^2 | Dose Level 6: 160 mg/m^2 | Dose Level 7: 200 mg/m^2 | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 6 Participants | 7 Participants | 7 Participants | 7 Participants | 5 Participants | 7 Participants | 45 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Continuous | 8 years | 5.5 years | 6 years | 6 years | 6 years | 5.5 years | 7 years | 6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 6 Participants | 6 Participants | 4 Participants | 7 Participants | 5 Participants | 6 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) White | 5 Participants | 4 Participants | 5 Participants | 3 Participants | 5 Participants | 2 Participants | 4 Participants | 28 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 3 Participants | 4 Participants | 5 Participants | 4 Participants | 4 Participants | 24 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 4 Participants | 3 Participants | 2 Participants | 2 Participants | 3 Participants | 22 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 6 | 4 / 6 | 4 / 7 | 4 / 7 | 6 / 7 | 4 / 6 | 4 / 7 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 7 / 7 | 7 / 7 | 7 / 7 | 6 / 6 | 7 / 7 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 2 / 7 | 2 / 7 | 2 / 7 | 2 / 6 | 1 / 7 |
Outcome results
Primary
Area Under the Time Concentration Curve of Adavosertib
Median (min, max) of the area under the concentration time curve adavosertib assessed at 1, 2, 4, 6, 8, and 24 hours post dose on day 1 stratified by dose level and study part.
Time frame: up to 24 hours
Population: All eligible patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Adavosertib) | Area Under the Time Concentration Curve of Adavosertib | 1122.2 hr*ng/mL |
| Dose Level 2: 50 mg/m^2 | Area Under the Time Concentration Curve of Adavosertib | 1233.3 hr*ng/mL |
| Dose Level 3: 50 mg/m^2 | Area Under the Time Concentration Curve of Adavosertib | 777.3 hr*ng/mL |
| Dose Level 4: 95 mg/m^2 | Area Under the Time Concentration Curve of Adavosertib | 2863.5 hr*ng/mL |
| Dose Level 5: 130 mg/m^2 | Area Under the Time Concentration Curve of Adavosertib | 2525.5 hr*ng/mL |
| Dose Level 6: 160 mg/m^2 | Area Under the Time Concentration Curve of Adavosertib | 5996.2 hr*ng/mL |
| Dose Level 7: 200 mg/m^2 | Area Under the Time Concentration Curve of Adavosertib | 5781.6 hr*ng/mL |
Primary
Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose of Adavosertib
MTD will be defined as the maximum dose at which fewer than one-third of patients experience a dose-limiting toxicity graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time frame: Up to 42 days
Population: All eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Adavosertib) | Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose of Adavosertib | 200 mg/m^2 |
Primary
Number of Dose Limiting Toxicity With Adavosertib
Number of patients with dose limiting toxicity stratified by dose level and the toxicity will be graded using the NCI CTCAE version 4.0.
Time frame: Up to 42 days
Population: All Toxicity evaluable patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Adavosertib) | Number of Dose Limiting Toxicity With Adavosertib | 0 Participants |
| Dose Level 2: 50 mg/m^2 | Number of Dose Limiting Toxicity With Adavosertib | 0 Participants |
| Dose Level 3: 50 mg/m^2 | Number of Dose Limiting Toxicity With Adavosertib | 0 Participants |
| Dose Level 4: 95 mg/m^2 | Number of Dose Limiting Toxicity With Adavosertib | 1 Participants |
| Dose Level 5: 130 mg/m^2 | Number of Dose Limiting Toxicity With Adavosertib | 0 Participants |
| Dose Level 6: 160 mg/m^2 | Number of Dose Limiting Toxicity With Adavosertib | 0 Participants |
| Dose Level 7: 200 mg/m^2 | Number of Dose Limiting Toxicity With Adavosertib | 1 Participants |
Secondary
Change in Expression of ɤ(Gamma)-H2AX of Adavosertib
Median (min, max) relative change in expression of gamma-H2AX of adavosertib by dose level and study part.
Time frame: Baseline to day 8
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Adavosertib) | Change in Expression of ɤ(Gamma)-H2AX of Adavosertib | 0.9 ratio |
| Dose Level 2: 50 mg/m^2 | Change in Expression of ɤ(Gamma)-H2AX of Adavosertib | 0.9 ratio |
| Dose Level 3: 50 mg/m^2 | Change in Expression of ɤ(Gamma)-H2AX of Adavosertib | 0.9 ratio |
| Dose Level 4: 95 mg/m^2 | Change in Expression of ɤ(Gamma)-H2AX of Adavosertib | 1.1 ratio |
| Dose Level 5: 130 mg/m^2 | Change in Expression of ɤ(Gamma)-H2AX of Adavosertib | 0.9 ratio |
| Dose Level 6: 160 mg/m^2 | Change in Expression of ɤ(Gamma)-H2AX of Adavosertib | 1 ratio |
| Dose Level 7: 200 mg/m^2 | Change in Expression of ɤ(Gamma)-H2AX of Adavosertib | 1.1 ratio |
Secondary
Change in Expression of p-HH3 of Adavosertib
Median (min, max) change in expression of p-HH3 in peripheral blood mononuclear cells (PBMCs) before and after administration by dose level and study part
Time frame: Baseline to day 8
Population: Data were not and will never be collected.
Secondary
Change in p-CDC2 of Adavosertib
Median (min, max) change in expression of p-CDC2 in peripheral blood mononuclear cells (PBMCs) before and after administration by dose level and study part.
Time frame: Baseline to day 8
Population: Data were not and will never be collected.
Secondary
Number of Patients With Response to Adavosertib
Number of participants with response (CR/PR) by maximal 2-dimensional measures with CR: disappearance of all abnormal signal within the brainstem; PR: at least 50% decrease in the sum o the products of the two perpendicular diameters of the target lesion.
Time frame: Up to 4 years
Population: All response evaluable patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Adavosertib) | Number of Patients With Response to Adavosertib | 0 Participants |
| Dose Level 2: 50 mg/m^2 | Number of Patients With Response to Adavosertib | 0 Participants |
| Dose Level 3: 50 mg/m^2 | Number of Patients With Response to Adavosertib | 0 Participants |
| Dose Level 4: 95 mg/m^2 | Number of Patients With Response to Adavosertib | 0 Participants |
| Dose Level 5: 130 mg/m^2 | Number of Patients With Response to Adavosertib | 0 Participants |
| Dose Level 6: 160 mg/m^2 | Number of Patients With Response to Adavosertib | 0 Participants |
| Dose Level 7: 200 mg/m^2 | Number of Patients With Response to Adavosertib | 0 Participants |
Secondary
Overall Survival (OS) of Adavosertib
Median (95% CI) time to progression or death stratified by dose level and study part.
Time frame: Up to 4 years
Population: All response evaluable patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Adavosertib) | Overall Survival (OS) of Adavosertib | 426.5 Days |
| Dose Level 2: 50 mg/m^2 | Overall Survival (OS) of Adavosertib | 250 Days |
| Dose Level 3: 50 mg/m^2 | Overall Survival (OS) of Adavosertib | 450.5 Days |
| Dose Level 4: 95 mg/m^2 | Overall Survival (OS) of Adavosertib | 372.5 Days |
| Dose Level 5: 130 mg/m^2 | Overall Survival (OS) of Adavosertib | 274 Days |
| Dose Level 6: 160 mg/m^2 | Overall Survival (OS) of Adavosertib | 273 Days |
| Dose Level 7: 200 mg/m^2 | Overall Survival (OS) of Adavosertib | 406 Days |
Secondary
Progression-free Survival (PFS) of Adavosertib
Median (95% CI) time to progression or death stratified by dose level and study part. PFS was defined as time from start date of the first treatment to the date of disease progression or death due to any causes which ever occurred first.
Time frame: Up to 4 years
Population: All response evaluable patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Adavosertib) | Progression-free Survival (PFS) of Adavosertib | 426.5 Days |
| Dose Level 2: 50 mg/m^2 | Progression-free Survival (PFS) of Adavosertib | 250 Days |
| Dose Level 3: 50 mg/m^2 | Progression-free Survival (PFS) of Adavosertib | 450.5 Days |
| Dose Level 4: 95 mg/m^2 | Progression-free Survival (PFS) of Adavosertib | 333 Days |
| Dose Level 5: 130 mg/m^2 | Progression-free Survival (PFS) of Adavosertib | 260 Days |
| Dose Level 6: 160 mg/m^2 | Progression-free Survival (PFS) of Adavosertib | 264 Days |
| Dose Level 7: 200 mg/m^2 | Progression-free Survival (PFS) of Adavosertib | 406 Days |