Advanced Malignant Solid Neoplasm, Fibrolamellar Carcinoma, Metastatic Malignant Solid Neoplasm, Ovarian Carcinoma, Pancreatic Neuroendocrine Tumor, Recurrent Malignant Solid Neoplasm, Refractory Malignant Solid Neoplasm, Unresectable Solid Neoplasm
Conditions
Brief summary
This phase I trial studies the side effects and best dose of sapanisertib and ziv-aflibercept in treating patients with solid tumors that have come back (recurrent) and have spread to another place in the body (metastatic) or cannot be removed by surgery (unresectable). Sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ziv-aflibercept may stop the growth of solid tumors by blocking the growth of new blood vessels necessary for tumor growth. Giving sapanisertib with ziv-aflibercept may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate safety and tolerability, determine maximum tolerated dose (MTD) and recommend a phase II dose of the combination of MLN0128 (TAK-228) (sapanisertib) with ziv-aflibercept in patients with advanced cancers refractory to standard therapy. SECONDARY OBJECTIVES: I. To give early indication of efficacy by evaluation of tumor size. II. To evaluate v-akt murine thymoma viral oncogene homolog 1 (Akt)/mechanistic target of rapamycin (serine/threonine kinase) (mTOR) signaling and adaptive responses; testing phosphorylation levels of biomarkers such as, but not limited to, vascular endothelial growth factor (VEGF)1 and 2, AKT and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) following treatment with MLN0128 (TAK-228) and ziv-aflibercept in peripheral blood mononuclear cells (PBMCs) and biopsy samples during expansion cohort. OUTLINE: This is a dose-escalation study. Patients receive sapanisertib orally (PO) once daily (QD) on days 2-4, 9-11, 16-18, and 23-25 and ziv-aflibercept intravenously (IV) over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.
Interventions
DRUGSapanisertib
Given PO
BIOLOGICALZiv-Aflibercept
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with advanced or metastatic cancer that is refractory to standard therapy or relapsed after standard therapy; patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective * Patients enrolled in the expansion cohort must have biopsiable disease; there will be preferential enrollment of patients with pancreatic neuroendocrine tumors or ovarian cancer during the dose expansion cohort * Patients must be \>= 4 weeks beyond treatment of any chemotherapy, other investigational therapy, hormonal, biological, targeted agents or radiotherapy, and must have recovered to =\< grade 1 toxicity or previous baseline for each toxicity; exception: patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy provided pelvis, sternum, scapulae, vertebrae, or skull were not included in the radiotherapy field * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 * Life expectancy of greater than 3 months * Leukocytes \>= 3,000/mcL * Absolute neutrophil count \>= 1,500/mcL * Platelets \>= 100,000/mcL * Hemoglobin \>= 9 g/dL * Total bilirubin =\< 1.5 x institutional upper limit of normal * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal * Creatinine =\< 1.5 x institutional upper limit of normal OR creatinine clearance \>= 60 mL/min for patients with creatinine levels above institutional normal * Fasting serum glucose =\< 130 mg/dL * Fasting triglycerides =\< 300 mg/dL * Glycosylated hemoglobin (HbA1c) \< 7.0% * Patients must have evaluable or measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * Women of child-bearing potential MUST have a negative serum or urine pregnancy test within 7 days unless prior hysterectomy or menopause (defined as 12 consecutive months without menstrual activity); patients should not become pregnant or breastfeed while on this study; women of child-bearing potential must agree to use 1 highly effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling \[e.g.; United Surgical Partners International (USPI), Summary of Product Characteristics (SmPC), etc;\]) after the last dose of study drug; or agree to practice true abstinence; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; male patients, even if surgically sterilized (i.e., status post-vasectomy), who: * Agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, or * Agree to completely abstain from heterosexual intercourse * Ability to understand and the willingness to sign a written informed consent document * Ability to swallow oral medications
Exclusion criteria
* Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered to =\< grade 1 adverse events due to agents administered more than 4 weeks earlier * Patients who are receiving any other investigational agents * Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events * History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN0128 (TAK-228) or ziv-aflibercept * Uncontrolled intercurrent illness including active infection * Pregnant women are excluded from this study because MLN0128 (TAK-228) and ziv-aflibercept are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MLN0128 (TAK-228) and ziv-aflibercept, breastfeeding should be discontinued if the mother is treated with MLN0128 (TAK-228) and ziv-aflibercept; these potential risks may also apply to other agents used in this study * Patients with known human immunodeficiency virus infection are not to be enrolled in the study * History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days or manifestations of malabsorption due to prior gastrointestinal (GI) surgery or GI disease that may alter the absorption of MLN0128 (TAK-228) * New York Heart Association class III or greater congestive heart failure within last 6 months or uncontrolled hyperlipidemia (cholesterol \> 300 mg/dl; triglyceride 2.5 X upper limit of normal \[ULN\] despite lipid lowering agent) within last 3 months * Uncontrolled diabetes (fasting serum glucose \> 130 mg/dl) despite best medical management or poorly controlled diabetes mellitus defined as hemoglobin (Hb)A1c \> 7%; subjects with a history of transient glucose intolerance due to corticosteroid administration are allowed in this study if all other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | DLT was assessed during Cycle 1 (28-day cycle). | DLTs were defined as adverse events per Common Terminology Criteria for Adverse Events version 4.0, related to study agents and fulfilling one of the following criteria: Hematologic * Grade 4 neutropenia for \> 7 days * Febrile neutropenia (defined as absolute neutrophil count \[ANC\] \< 1.0 x 109/L and fever ≥ 38.5° C) or grade ≥3 infection with ANC≤1.0 x 109/L. * Platelet count \< 25,000/mm for \> 7 days Non-hematologic * Any toxicity ≥grade 3 that persists for \> 7 days, except: 1. nausea/vomiting, diarrhea and electrolyte imbalances; 2. grade 3 lab abnormalities that are asymptomatic and responsive to supportive measures and that are without clinical consequence; and 3. grade 3 hyperglycemia or grade 3 diabetes that can be stably controlled. * Delay of treatment \> 7 days due to hematologic and \> 14 days due to non-hematologic toxicity MTD is the highest dose level at which no more than 1 of 6 evaluable patients had a DLT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | At baseline and every 8 weeks. Confirmatory scans done 8 (not less than 4) weeks following initial documentation of objective response. If a patient has been on the study for 12 months, the response was evaluated every 12 weeks, assessed up to 3 years. | Tumor response by change in tumor size from baseline assessed by Objective response rate was defined as the percentage of patients who had complete response (CR) or partial response (PR) according to RECIST v1.1. |
| Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | At baseline and every 8 weeks. Confirmatory scans done 8 (not less than 4) weeks following initial documentation of objective response. If a patient has been on the study for 12 months, the response was evaluated every 12 weeks, assessed up to 3 years. | Tumor response by change in tumor size from baseline assessed by Disease control rate was defined as the percentage of patients who had CR or PR or stable disease (SD) according to RECIST v1.1. |
Countries
United States
Participant flow
Recruitment details
This is an open label, Phase I trial examining MLN0128 in Combination with Ziv-Aflibercept in patients with advanced cancers at The University of Texas MD Anderson Cancer Center.
Pre-assignment details
Of the 83 patients, only 55 patients received at least 1 dose of the study agents. The remaining 28 patients screen failed and did not receive any dose of the study drugs. Per the protocol, all 55 patients who received one or more doses of drug were included in the analysis and the results are reported here.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 MLN0128 (mg PO): 3 QD Ziv-Aflibercept (mg/kg IV Q2 weeks): 3 | 5 |
| Dose Level 1b MLN0128 (mg PO): 3 (3 days on/4 days off) Ziv-Aflibercept (mg/kg IV Q2 weeks): 2 | 4 |
| Dose Level 2 MLN0128 (mg PO): 3 (3 days on/4 days off) Ziv-Aflibercept (mg/kg IV Q2 weeks): 3 | 3 |
| Dose Level 3 MLN0128 (mg PO): 4 (3 days on/4 days off) Ziv-Aflibercept (mg/kg IV Q2 weeks): 3 | 3 |
| Dose Level 4 MLN0128 (mg PO): 4 (3 days on/4 days off) Ziv-Aflibercept (mg/kg IV Q2 weeks): 4 | 4 |
| Dose Level 5 MLN0128 (mg PO): 5 (3 days on/4 days off) Ziv-Aflibercept (mg/kg IV Q2 weeks): 4 | 3 |
| Dose Level 6 MLN0128 (mg PO): 6 (3 days on/4 days off) Ziv-Aflibercept (mg/kg IV Q2 weeks): 4 | 7 |
| Dose Level 5a MLN0128 (mg PO): 5 (3 days on/4 days off) Ziv-Aflibercept (mg/kg IV Q2 weeks): 3 | 4 |
| Dose Level 4a MLN0128 (mg PO): 4 (3 days on/4 days off) Ziv-Aflibercept (mg/kg IV Q2 weeks): 2 | 3 |
| Dose Level 2a MLN0128 (mg PO): 4 (3 days on/4 days off) Ziv-Aflibercept (mg/kg IV Q2 weeks): 3 | 9 |
| Dose Level 2a Expansion MLN0128 (mg PO): 4 (3 days on/4 days off) Ziv-Aflibercept (mg/kg IV Q2 weeks): 3 | 10 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 1 | 0 | 1 | 2 | 0 | 2 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Insurance Issues | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 2 | 3 | 3 | 0 | 2 | 3 | 3 | 1 | 3 | 6 | 7 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | New treatment | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 2 | 1 | 0 | 3 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Dose Level 1b | Dose Level 2 | Dose Level 3 | Dose Level 4 | Dose Level 5 | Dose Level 6 | Dose Level 1 | Dose Level 5a | Dose Level 4a | Dose Level 2a | Dose Level 2a Expansion |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 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 |
| Age, Categorical >=65 years | 20 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 2 Participants | 1 Participants | 8 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 5 Participants | 2 Participants | 2 Participants | 3 Participants | 7 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 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 |
| Race (NIH/OMB) Asian | 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) Black or African American | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 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 |
| 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 |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 46 Participants | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 6 Participants | 5 Participants | 2 Participants | 3 Participants | 7 Participants | 8 Participants |
| Region of Enrollment United States | 55 participants | 4 participants | 3 participants | 3 participants | 4 participants | 3 participants | 7 participants | 5 participants | 4 participants | 3 participants | 9 participants | 10 participants |
| Sex: Female, Male Female | 40 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 5 Participants | 3 Participants | 3 Participants | 7 Participants | 7 Participants |
| Sex: Female, Male Male | 15 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 5 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 5 | 4 / 4 | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 7 / 7 | 4 / 4 | 3 / 3 | 7 / 9 | 8 / 10 |
| other Total, other adverse events | 5 / 5 | 4 / 4 | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 7 / 7 | 4 / 4 | 3 / 3 | 9 / 9 | 10 / 10 |
| serious Total, serious adverse events | 4 / 5 | 2 / 4 | 1 / 3 | 0 / 3 | 3 / 4 | 2 / 3 | 4 / 7 | 3 / 4 | 2 / 3 | 4 / 9 | 2 / 10 |
Outcome results
Primary
Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD)
DLTs were defined as adverse events per Common Terminology Criteria for Adverse Events version 4.0, related to study agents and fulfilling one of the following criteria: Hematologic * Grade 4 neutropenia for \> 7 days * Febrile neutropenia (defined as absolute neutrophil count \[ANC\] \< 1.0 x 109/L and fever ≥ 38.5° C) or grade ≥3 infection with ANC≤1.0 x 109/L. * Platelet count \< 25,000/mm for \> 7 days Non-hematologic * Any toxicity ≥grade 3 that persists for \> 7 days, except: 1. nausea/vomiting, diarrhea and electrolyte imbalances; 2. grade 3 lab abnormalities that are asymptomatic and responsive to supportive measures and that are without clinical consequence; and 3. grade 3 hyperglycemia or grade 3 diabetes that can be stably controlled. * Delay of treatment \> 7 days due to hematologic and \> 14 days due to non-hematologic toxicity MTD is the highest dose level at which no more than 1 of 6 evaluable patients had a DLT
Time frame: DLT was assessed during Cycle 1 (28-day cycle).
Population: Patients enrolled in the dose escalation phase must have received at least 75% of planned doses of both drugs to be evaluable for a DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 1b | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 2 | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 3 | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 4 | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 5 | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 6 | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 2 Participants |
| Dose Level 5a | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 1 Participants |
| Dose Level 4a | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 2a | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 2a Expansion | Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
Secondary
Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1
Tumor response by change in tumor size from baseline assessed by Disease control rate was defined as the percentage of patients who had CR or PR or stable disease (SD) according to RECIST v1.1.
Time frame: At baseline and every 8 weeks. Confirmatory scans done 8 (not less than 4) weeks following initial documentation of objective response. If a patient has been on the study for 12 months, the response was evaluated every 12 weeks, assessed up to 3 years.
Population: Only those patients who had measurable disease present at baseline, had received at least one cycle of therapy, and have had their disease re-evaluated were considered evaluable for response
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 2 Participants |
| Dose Level 1b | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 3 Participants |
| Dose Level 2 | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 3 Participants |
| Dose Level 3 | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 3 Participants |
| Dose Level 4 | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 4 Participants |
| Dose Level 5 | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 2 Participants |
| Dose Level 6 | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 4 Participants |
| Dose Level 5a | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 2 Participants |
| Dose Level 4a | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 3 Participants |
| Dose Level 2a | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 7 Participants |
| Dose Level 2a Expansion | Tumor Response by Change in Tumor Size From Baseline: Disease Control Rate Per RECIST v1.1 | 6 Participants |
Secondary
Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1
Tumor response by change in tumor size from baseline assessed by Objective response rate was defined as the percentage of patients who had complete response (CR) or partial response (PR) according to RECIST v1.1.
Time frame: At baseline and every 8 weeks. Confirmatory scans done 8 (not less than 4) weeks following initial documentation of objective response. If a patient has been on the study for 12 months, the response was evaluated every 12 weeks, assessed up to 3 years.
Population: Only those patients who had measurable disease present at baseline, had received at least one cycle of therapy, and have had their disease re-evaluated were considered evaluable for response
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Dose Level 1b | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Dose Level 2 | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Dose Level 3 | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Dose Level 4 | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 1 Participants |
| Dose Level 5 | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Dose Level 6 | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Dose Level 5a | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Dose Level 4a | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Dose Level 2a | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Dose Level 2a Expansion | Tumor Response by Change in Tumor Size From Baseline: Objective Response Rate Per RECIST v1.1 | 1 Participants |