Resectable Soft Tissue Sarcoma, Soft Tissue Sarcoma
Conditions
Brief summary
This phase Ib trial studies the side effects of navtemadlin and radiation therapy in treating patients with soft tissue sarcoma. Navtemadlin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving navtemadlin and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of navtemadlin (AMG-232 \[KRT-232\]) in combination with standard-dose radiotherapy in soft tissue sarcoma (STS) in two separate patient cohorts (A, extremity or body wall; B, abdomen/pelvis/retroperitoneum). II. To determine the maximum tolerated dose/recommended phase II dose (maximum tolerated dose/recommended phase 2 dosage \[MTD/RP2D\]) of AMG 232 (KRT-232) in combination with radiotherapy. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To determine percentage (%) necrosis and pathologic complete response (pCR) in final surgical resection specimen. III. To determine % local failure (LF), disease free survival (DFS) and overall survival (OS) at 2 years. IV. To determine pharmacodynamics (PD) effects of AMG 232 (KRT-232) when combined with radiotherapy by assessing serial serum macrophage inhibitory cytokine (MIC)-1 levels. V. To determine AMG 232 (KRT-232) exposure (pharmacokinetics)-response relationships (PD, toxicity, and efficacy). EXPLORATORY OBJECTIVES: I. To determine tumor volume changes determined by magnetic resonance imaging (MRI) or computed tomography (CT) with and without contrast pre- and post-radiotherapy. II. To characterize clinical outcomes in patients treated with AMG 232 (KRT-232) by genomic biomarkers. III. To determine the correlation between mdm2/4 expression determined by next-generation sequencing (NGS) and the protein levels by immunohistochemistry (IHC). IV. To explore the possibility of identifying tumor genetic mutations in (1) cell-free (cf) circulating tumor deoxyribonucleic acid (ctDNA), (2) deoxyribonucleic acid/ribonucleic acid (DNA/RNA) isolated from exosomes, and determine the concordance of these results and that from NGS. OUTLINE: This is a dose-escalation study of navtemadlin. STEP 1: Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin orally (PO) on days 2-4, days 2-5, or days 1-5 of weeks 1 to 5 in the absence of disease progression or unacceptable toxicity. STEP 2: Patients with a wild-type p53 gene status are assigned to Group I, while patients with deleted/mutant p53 gene status are assigned to Group II. GROUP I: Starting with week 2, patients receive navtemadlin as in Step 1 and undergo radiation therapy (RT) daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion. GROUP II: Starting with week 2, patients undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion. After completion of study treatment, patients are followed up every 3 months for 2 years, and then at 2.5 years.
Interventions
PROCEDURESurgical Procedure
Undergo surgery
DRUGNavtemadlin
Given PO
RADIATIONRadiation Therapy
Undergo radiation therapy
Sponsors
NRG Oncology
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA * Patients with pathologically proven diagnosis of grade 2-3 (intermediate or high grade) soft tissue sarcoma with size \>= 5 cm are eligible to enroll if the intention to treat is curative. They must have sufficient tissue to submit to central laboratory for review as well as for NGS sequencing (see submission requirement). Biopsy should be obtained within 180 days prior to registration. Availability of tumor tissue is mandatory for study eligibility. The patient must have consented to provide archived formalin-fixed paraffin-embedded tumor tissue for future central pathology review, NGS sequencing and/or translational research * Appropriate stage for study entry based on the following diagnostic workup: * History/physical examination within 30 days prior to registration; * Imaging of the primary tumor by MRI and/or computed tomography (CT) with or without contrast and/or positron emission tomography (PET)/CT within 30 days prior to registration; * Staging workup evaluated by chest CT and/or PET/CT showing no distant metastasis within 30 days prior to registration * There is a planned definitive surgical resection of the primary tumor * Eastern Cooperative Oncology Group (ECOG) or Zubrod performance status of 0-1 within 30 days prior to registration * Absolute neutrophil count \>= 1500/uL (within 30 days prior to registration) * Platelet count \>= 100,000/uL (within 30 days prior to registration) * Hemoglobin: \>= 10 g/dL (transfuse as necessary to raise levels; no transfusions within 7 days of start) (within 30 days prior to registration) * Calculated creatinine clearance \>= 60 ml/min (by Cockcroft-Gault formula) within 30 days prior to registration * The patient has an adequate coagulation function as defined by international normalized ratio (INR) =\< 1.5 x upper limit of normal (ULN) or prothrombin time (PT) =\< 1.5 x ULN, and partial thromboplastin time (PTT or aPTT) =\< 1.5 x ULN (those receiving anticoagulation therapy except low molecular weight heparin are excluded) (within 30 days prior to registration) * Total bilirubin =\< 1.5 x upper limit of normal (ULN) appropriate for age (except for patients with Gilbert's syndrome, who must have a total bilirubin \< 3 mg/dL) (within 30 days prior to registration) * Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase (AST) or serum glutamate pyruvate transaminase (SGPT) alanine aminotransaminase (ALT) \< 2.5 upper limit of normal (ULN) appropriate for age (within 30 days prior to registration) * Females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; exceptions: females not of child-bearing potential due to surgical sterilization (at least 6 weeks following tubal ligation, hysterectomy, or surgical bilateral oophorectomy with or without hysterectomy) confirmed by medical history; or female after menopause * A postmenopausal woman is a woman meeting either of the following criteria: * Spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as anorexia nervosa and not taking medications during the amenorrhea that induced the amenorrhea (for example, oral contraceptives, hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen receptor modulators \[SERMs\], or chemotherapy) * Spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone (FSH) level \> 40 mIU/mL * Females of child-bearing potential and males must agree to use highly effective contraceptive precautions during the trial and up to 12 months following the last dose of study treatment; a highly effective method of birth control is defined as one that results in a low failure rate (that is, \< 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner * The patient or a legally authorized representative must provide study-specific informed consent prior to study entry * PRIOR TO STEP 2 REGISTRATION INCLUSION CRITERIA * TP53 sequencing by NGS performed by central pathology lab
Exclusion criteria
* PRIOR TO STEP 1 REGISTRATION
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) / Recommended Phase 2 Dosage for Each Cohort | Baseline to end of navtemadlin + 4 weeks (approximately 10 weeks total) | Dose was determined separately for each cohort using the classic 3+3 design to determine the safety of each dose level from the number of participants with dose limiting toxicities (DLTs), starting with dose level 1. If dose level 1 were considered unsafe, a lower dose level of twice/week would be tested. The highest dose level deemed safe is considered the MTD. Five additional patients were accrued to the MTD to ensure safety. A DLT is defined as any grade 4-5 adverse event (AE) using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) that was definitely, probably, or possibly (DPP) related to navtemadlin or combined navtemadlin+RT ≤ 4 weeks after completing navtemadlin. Any grade 3 AE DPP related to navtemadlin/navtemadlin+RT was also considered a DLT if due to the grade 3 AE there was a delay of \>2 weeks or if there were ≥ 2 dose reductions. CTCAE 5.0 Grade 3 is a severe AE, Grade 4 is a life-threatening or disabling AE, and Grade 5 results in death. |
| Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) | Baseline to end of navtemadlin + 4 weeks (approximately 10 weeks total) | A DLT is defined as any grade 4-5 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) that was definitely, probably, or possibly related to navtemadlin or combined navtemadlin+RT up to 4 weeks after the completion of navtemadlin. Any grade 3 AE definitely, probably, or possibly related to navtemadlin or combined navtemadlin+RT was also considered DLT if any of the 2 following situations occurred: a delay of \>2 weeks due to the grade 3 AE, or ≥ 2 dose reductions due to the grade 3 AE. CTCAE 5.0 Grade 3 is a severe AE, Grade 4 is a life-threatening or disabling AE, and Grade 5 results in death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Local Failure | Baseline to the date of failure or last known follow-up, up to 2.5 years from end of RT (six weeks). | Local failure (LF) was defined as local recurrence or progression after surgery, or amputation for treatment complications or recurrence/progression. In addition, any patient that did not have surgery was considered to have local failure. Local progression was defined as at lease 20% increase in the maximal dimension of the primary tumor taking as reference the smallest maximal dimension recorded since treatment started. |
| Number of Participants With Disease or Death From Any Cause | Baseline to the date of disease, death, or last known follow-up, up to 2.5 years from end of RT (six weeks). | Disease is defined as any of the following: Local, regional, or distant disease. * Local disease: tumor recurrence or progression. Progression is defined as at 20% increase in the maximal dimension of the primary tumor taking as reference the smallest maximal dimension recorded since treatment started; * Regional disease: Any nodal metastasis adjacent to the primary soft tissue sarcoma; * Distant disease: Any tumor that develops distantly from the primary site of sarcoma; * Amputation for treatment complications or recurrence/progression. * Failure to continue to surgery. |
| Number of Participants Who Died | Baseline to the date of death or last known follow-up, up to 2.5 years from end of RT (six weeks). | Death from any cause |
| Serial Serum Macrophage Inhibitory Cytokine-1 Levels | Up to 2.5 years | Will be tabulated and descriptive statistics and calculated for each dose level. |
| Navtemadlin Exposure-response Relationships | Up to 2.5 years | — |
| Percent of Necrosis in Final Surgical Resection Specimen | At time of surgery (approximately 11 to 14 weeks) | The evaluation for pathologic response will include a formal evaluation of percent necrosis according to the guidelines established for osteosarcoma and is determined by central pathological review. |
| Number of Participants With Pathologic Complete Response (PCR) in Final Surgical Resection Specimen | At time of surgery (approximately 11 to 14 weeks) | Pathologic complete response is defined as 100% necrosis and is determined by central pathology review. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Tumor Genetic Mutations in Deoxyribonucleic Acid Ribonucleic Acid Isolated From Exosomes | Up to 2.5 years | — |
| mdm2/4 Expression | Up to 2.5 years | Will be correlated with protein levels and assessed using Pearson's correlation. |
| Clinical Outcomes by Genomic Biomarkers | Up to 2.5 years | — |
| Tumor Volume Changes | Up to 2.5 years | Will be compared by paired t test. |
Countries
United States
Participant flow
Pre-assignment details
This is a two-step study in which all participants start one week of treatment at Step 1 at the current dose escalation level while p53 status is determined, but Step 2 assigns the full/remaining course of treatment and determines the intended analysis population: participants with wild-type p53 (Group I) continue on navtemadlin for the purpose of the study analysis, while the rest of participants (Group II) discontinue navtemadlin and are not included in endpoint analyses.
Participants by arm
| Arm | Count |
|---|---|
| Group I: Cohort A: Dose Level 1 (3x/Week) Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 2-4 of week 1 in the absence of disease progression or unacceptable toxicity. (Step 1) Starting with week 2, patients receive navtemadlin as in Step 1 and undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
Group I = wild-type p53 status. Cohort A = Patients with extremity/body wall soft tissue sarcoma. | 3 |
| Group I: Dose Level 2 (4x/Week) Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 2-5 of week 1 in the absence of disease progression or unacceptable toxicity. (Step 1) Starting with week 2, patients receive navtemadlin as in Step 1 and undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
Group I = wild-type p53 status. Cohort A = Patients with extremity/body wall soft tissue sarcoma. | 4 |
| Group I: Cohort A: Dose Level 3 (5x/Week) Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 1-5 of week 1 in the absence of disease progression or unacceptable toxicity. (Step 1) Starting with week 2, patients receive navtemadlin as in Step 1 and undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
Group I = wild-type p53 status. Cohort A = Patients with extremity/body wall soft tissue sarcoma.wall soft tissue sarcoma. | 9 |
| Group I: Cohort B: Dose Level 1 (3x/Week) Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 2-4 of week 1 in the absence of disease progression or unacceptable toxicity. (Step 1) Starting with week 2, patients receive navtemadlin as in Step 1 and undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
Group I = wild-type p53 status. Cohort B = Patients with abdomen/pelvis/retroperitoneum soft tissue sarcoma. | 3 |
| Group I: Cohort B: Dose Level 2 (4x/Week) Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 2-5 of week 1 in the absence of disease progression or unacceptable toxicity. (Step 1) Starting with week 2, patients receive navtemadlin as in Step 1 and undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
Group I = wild-type p53 status. Cohort B = Patients with abdomen/pelvis/retroperitoneum soft tissue sarcoma. | 3 |
| Group II: Cohort A: Level 2 (4x/Week) Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 2-5 of week 1 in the absence of disease progression or unacceptable toxicity. Starting with week 2, patients undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion. Group II = mutant or unknown p53 status. Cohort A = Patients with extremity/body wall soft tissue sarcoma. | 2 |
| Group II: Cohort A: Dose Level 3 (5x/Week) Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 1-5 of week 1 in the absence of disease progression or unacceptable toxicity. Starting with week 2, patients undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion. Group II = mutant or unknown p53 status. Cohort A = Patients with extremity/body wall soft tissue sarcoma. | 6 |
| Group II: Cohort B: Dose Level 1 (3x/Week) Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 2-4 of week 1 in the absence of disease progression or unacceptable toxicity. Starting with week 2, patients undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion. Group II = mutant or unknown p53 status. Cohort B = Patients with abdomen/pelvis/retroperitoneum soft tissue sarcoma. | 2 |
| Group II: Cohort B: Dose Level 2 (4x/Week) Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin PO on days 2-5 of week 1 in the absence of disease progression or unacceptable toxicity. Starting with week 2, patients undergo radiation therapy daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion. Group II = mutant or unknown p53 status. Cohort B = Patients with abdomen/pelvis/retroperitoneum soft tissue sarcoma. | 2 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Step 1: Dose Level 1 | Did not start protocol treatment | 1 | 0 | 0 | 0 |
| Step 1: Dose Level 2 | Did not start protocol treatment | 1 | 2 | 0 | 0 |
| Step 1: Dose Level 3 | Did not start treatment | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Group I: Dose Level 2 (4x/Week) | Group I: Cohort A: Dose Level 3 (5x/Week) | Group I: Cohort B: Dose Level 1 (3x/Week) | Group I: Cohort B: Dose Level 2 (4x/Week) | Group II: Cohort A: Level 2 (4x/Week) | Group I: Cohort A: Dose Level 1 (3x/Week) | Group II: Cohort A: Dose Level 3 (5x/Week) | Group II: Cohort B: Dose Level 1 (3x/Week) | Group II: Cohort B: Dose Level 2 (4x/Week) | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized ≤ 49 years | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 6 Participants |
| Age, Customized 50 - 59 years | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 6 Participants |
| Age, Customized 60 -69 years | 4 Participants | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 3 Participants | 3 Participants | 1 Participants | 0 Participants | 16 Participants |
| Age, Customized ≥ 70 years | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 8 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 5 Participants | 2 Participants | 2 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Histologic Grade from Central Review Grade II | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 8 Participants |
| Histologic Grade from Central Review Grade III | 4 Participants | 7 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 5 Participants | 2 Participants | 1 Participants | 25 Participants |
| Histology from Central Review Dedifferentiated liposarcoma | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 7 Participants |
| Histology from Central Review Extraskeletal myxoid chondrosarcoma | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Histology from Central Review Leiomyosarcoma | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Histology from Central Review Liposarcoma, not otherwise specified | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Histology from Central Review Malignant peripheral nerve sheath tumor | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Histology from Central Review Myxofibrosarcoma | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants |
| Histology from Central Review Myxoid liposarcoma | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Histology from Central Review Solitary fibrous tumor | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Histology from Central Review Synovial sarcoma | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Histology from Central Review Undifferentiated pleomorphic sarcoma | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 7 Participants |
| Histology from Central Review Undifferentiated spindle cell sarcoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Primary tumor site Abdomen | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Primary tumor site Back | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Primary tumor site Buttock | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Primary tumor site Distal Lower Extremity | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 5 Participants |
| Primary tumor site Distal Upper Extremity | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Primary tumor site Pelvis | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Primary tumor site Proximal Lower Extremity | 3 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 10 Participants |
| Primary tumor site Proximal Upper Extremity | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Primary tumor site Retroperitoneum | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 7 Participants |
| Primary tumor site Shoulder | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 3 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 |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 2 Participants | 7 Participants | 3 Participants | 0 Participants | 2 Participants | 3 Participants | 5 Participants | 2 Participants | 1 Participants | 25 Participants |
| Sex: Female, Male Female | 1 Participants | 6 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 1 Participants | 19 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 15 Participants |
| Tumor size (cm) 10 - < 15 cm | 1 Participants | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 14 Participants |
| Tumor size (cm) ≥ 15 cm | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 8 Participants |
| Tumor size (cm) 5 - < 10 cm | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 1 Participants | 12 Participants |
| Zubrod performance status 0 | 2 Participants | 7 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants | 2 Participants | 1 Participants | 22 Participants |
| Zubrod performance status 1 | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 12 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 |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 4 | 1 / 9 | 1 / 3 | 1 / 3 | 1 / 2 | 0 / 6 | 1 / 2 | 0 / 2 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 9 / 9 | 3 / 3 | 3 / 3 | 2 / 2 | 6 / 6 | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 2 / 3 | 4 / 4 | 5 / 9 | 3 / 3 | 3 / 3 | 1 / 2 | 1 / 6 | 1 / 2 | 1 / 2 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) / Recommended Phase 2 Dosage for Each Cohort
Dose was determined separately for each cohort using the classic 3+3 design to determine the safety of each dose level from the number of participants with dose limiting toxicities (DLTs), starting with dose level 1. If dose level 1 were considered unsafe, a lower dose level of twice/week would be tested. The highest dose level deemed safe is considered the MTD. Five additional patients were accrued to the MTD to ensure safety. A DLT is defined as any grade 4-5 adverse event (AE) using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) that was definitely, probably, or possibly (DPP) related to navtemadlin or combined navtemadlin+RT ≤ 4 weeks after completing navtemadlin. Any grade 3 AE DPP related to navtemadlin/navtemadlin+RT was also considered a DLT if due to the grade 3 AE there was a delay of \>2 weeks or if there were ≥ 2 dose reductions. CTCAE 5.0 Grade 3 is a severe AE, Grade 4 is a life-threatening or disabling AE, and Grade 5 results in death.
Time frame: Baseline to end of navtemadlin + 4 weeks (approximately 10 weeks total)
Population: Eligible wild-type p53 participants who either received at least one dose of navtemadlin if there was a dose limiting toxicity (DLT), or, in the absence of DLT, received at least one fraction of RT and completed DLT observation period (4 weeks after completion of navtemadlin). Step 2 Group I participants (Group I = wild-type p53 status).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Maximum Tolerated Dose (MTD) / Recommended Phase 2 Dosage for Each Cohort | 5 times per week of 125mg PO |
| Cohort B | Maximum Tolerated Dose (MTD) / Recommended Phase 2 Dosage for Each Cohort | NA times per week of 125mg PO |
Primary
Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)
A DLT is defined as any grade 4-5 adverse event (AE) using the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) that was definitely, probably, or possibly related to navtemadlin or combined navtemadlin+RT up to 4 weeks after the completion of navtemadlin. Any grade 3 AE definitely, probably, or possibly related to navtemadlin or combined navtemadlin+RT was also considered DLT if any of the 2 following situations occurred: a delay of \>2 weeks due to the grade 3 AE, or ≥ 2 dose reductions due to the grade 3 AE. CTCAE 5.0 Grade 3 is a severe AE, Grade 4 is a life-threatening or disabling AE, and Grade 5 results in death.
Time frame: Baseline to end of navtemadlin + 4 weeks (approximately 10 weeks total)
Population: Eligible wild-type p53 participants who either received at least one dose of navtemadlin if there was a dose limiting toxicity (DLT), or, in the absence of DLT, received at least one fraction of RT and completed DLT observation period (4 weeks after completion of navtemadlin).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) | 0 Participants |
| Cohort B | Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) | 0 Participants |
| Cohort A: Dose Level 3 (5x/Week) | Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) | 0 Participants |
| Cohort B: Dose Level 1 (3x/Week) | Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) | 0 Participants |
| Cohort B: Dose Level 2 (4x/Week) | Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) | 1 Participants |
Secondary
Navtemadlin Exposure-response Relationships
Time frame: Up to 2.5 years
Secondary
Number of Participants Who Died
Death from any cause
Time frame: Baseline to the date of death or last known follow-up, up to 2.5 years from end of RT (six weeks).
Population: Eligible Group I (wild-type p53) participants who started protocol treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Number of Participants Who Died | 0 Participants |
| Cohort B | Number of Participants Who Died | 1 Participants |
| Cohort A: Dose Level 3 (5x/Week) | Number of Participants Who Died | 1 Participants |
| Cohort B: Dose Level 1 (3x/Week) | Number of Participants Who Died | 1 Participants |
| Cohort B: Dose Level 2 (4x/Week) | Number of Participants Who Died | 1 Participants |
Secondary
Number of Participants With Disease or Death From Any Cause
Disease is defined as any of the following: Local, regional, or distant disease. * Local disease: tumor recurrence or progression. Progression is defined as at 20% increase in the maximal dimension of the primary tumor taking as reference the smallest maximal dimension recorded since treatment started; * Regional disease: Any nodal metastasis adjacent to the primary soft tissue sarcoma; * Distant disease: Any tumor that develops distantly from the primary site of sarcoma; * Amputation for treatment complications or recurrence/progression. * Failure to continue to surgery.
Time frame: Baseline to the date of disease, death, or last known follow-up, up to 2.5 years from end of RT (six weeks).
Population: Eligible Group I (wild-type p53) participants who started protocol treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Number of Participants With Disease or Death From Any Cause | 1 Participants |
| Cohort B | Number of Participants With Disease or Death From Any Cause | 2 Participants |
| Cohort A: Dose Level 3 (5x/Week) | Number of Participants With Disease or Death From Any Cause | 4 Participants |
| Cohort B: Dose Level 1 (3x/Week) | Number of Participants With Disease or Death From Any Cause | 1 Participants |
| Cohort B: Dose Level 2 (4x/Week) | Number of Participants With Disease or Death From Any Cause | 1 Participants |
Secondary
Number of Participants With Local Failure
Local failure (LF) was defined as local recurrence or progression after surgery, or amputation for treatment complications or recurrence/progression. In addition, any patient that did not have surgery was considered to have local failure. Local progression was defined as at lease 20% increase in the maximal dimension of the primary tumor taking as reference the smallest maximal dimension recorded since treatment started.
Time frame: Baseline to the date of failure or last known follow-up, up to 2.5 years from end of RT (six weeks).
Population: Eligible Group I (wild-type p53) participants who started protocol treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Number of Participants With Local Failure | 1 Participants |
| Cohort B | Number of Participants With Local Failure | 2 Participants |
| Cohort A: Dose Level 3 (5x/Week) | Number of Participants With Local Failure | 2 Participants |
| Cohort B: Dose Level 1 (3x/Week) | Number of Participants With Local Failure | 1 Participants |
| Cohort B: Dose Level 2 (4x/Week) | Number of Participants With Local Failure | 1 Participants |
Secondary
Number of Participants With Pathologic Complete Response (PCR) in Final Surgical Resection Specimen
Pathologic complete response is defined as 100% necrosis and is determined by central pathology review.
Time frame: At time of surgery (approximately 11 to 14 weeks)
Population: Eligible Group I (wild-type p53) participants who started protocol treatment and had central pathological review of their final surgical resection specimen.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Number of Participants With Pathologic Complete Response (PCR) in Final Surgical Resection Specimen | 0 Participants |
| Cohort B | Number of Participants With Pathologic Complete Response (PCR) in Final Surgical Resection Specimen | 0 Participants |
| Cohort A: Dose Level 3 (5x/Week) | Number of Participants With Pathologic Complete Response (PCR) in Final Surgical Resection Specimen | 0 Participants |
| Cohort B: Dose Level 1 (3x/Week) | Number of Participants With Pathologic Complete Response (PCR) in Final Surgical Resection Specimen | 0 Participants |
| Cohort B: Dose Level 2 (4x/Week) | Number of Participants With Pathologic Complete Response (PCR) in Final Surgical Resection Specimen | 0 Participants |
Secondary
Percent of Necrosis in Final Surgical Resection Specimen
The evaluation for pathologic response will include a formal evaluation of percent necrosis according to the guidelines established for osteosarcoma and is determined by central pathological review.
Time frame: At time of surgery (approximately 11 to 14 weeks)
Population: Eligible Group I (wild-type p53) participants who started protocol treatment and had central pathological review of their final surgical resection specimen.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Percent of Necrosis in Final Surgical Resection Specimen | <25% | 2 Participants |
| Cohort A | Percent of Necrosis in Final Surgical Resection Specimen | 50-75% | 0 Participants |
| Cohort A | Percent of Necrosis in Final Surgical Resection Specimen | 25-49% | 1 Participants |
| Cohort A | Percent of Necrosis in Final Surgical Resection Specimen | 76-99% | 0 Participants |
| Cohort B | Percent of Necrosis in Final Surgical Resection Specimen | 25-49% | 2 Participants |
| Cohort B | Percent of Necrosis in Final Surgical Resection Specimen | <25% | 0 Participants |
| Cohort B | Percent of Necrosis in Final Surgical Resection Specimen | 50-75% | 0 Participants |
| Cohort B | Percent of Necrosis in Final Surgical Resection Specimen | 76-99% | 0 Participants |
| Cohort A: Dose Level 3 (5x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | 25-49% | 1 Participants |
| Cohort A: Dose Level 3 (5x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | 76-99% | 2 Participants |
| Cohort A: Dose Level 3 (5x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | <25% | 3 Participants |
| Cohort A: Dose Level 3 (5x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | 50-75% | 2 Participants |
| Cohort B: Dose Level 1 (3x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | 76-99% | 0 Participants |
| Cohort B: Dose Level 1 (3x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | 25-49% | 1 Participants |
| Cohort B: Dose Level 1 (3x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | 50-75% | 0 Participants |
| Cohort B: Dose Level 1 (3x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | <25% | 2 Participants |
| Cohort B: Dose Level 2 (4x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | <25% | 1 Participants |
| Cohort B: Dose Level 2 (4x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | 25-49% | 0 Participants |
| Cohort B: Dose Level 2 (4x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | 50-75% | 0 Participants |
| Cohort B: Dose Level 2 (4x/Week) | Percent of Necrosis in Final Surgical Resection Specimen | 76-99% | 0 Participants |
Secondary
Serial Serum Macrophage Inhibitory Cytokine-1 Levels
Will be tabulated and descriptive statistics and calculated for each dose level.
Time frame: Up to 2.5 years
Other Pre-specified
Clinical Outcomes by Genomic Biomarkers
Time frame: Up to 2.5 years
Other Pre-specified
mdm2/4 Expression
Will be correlated with protein levels and assessed using Pearson's correlation.
Time frame: Up to 2.5 years
Other Pre-specified
Tumor Genetic Mutations in Deoxyribonucleic Acid Ribonucleic Acid Isolated From Exosomes
Time frame: Up to 2.5 years
Other Pre-specified
Tumor Volume Changes
Will be compared by paired t test.
Time frame: Up to 2.5 years