Navtemadlin and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma

Phase 1

Active, not recruiting

Conditions: Resectable Soft Tissue Sarcoma
Soft Tissue Sarcoma

Interventions: Drug: Navtemadlin
Radiation: Radiation Therapy
Procedure: Surgical Procedure

Registration Number: NCT03217266

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 39

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 EXCLUSION CRITERIA
Well-differentiated liposarcoma or other low grade STS; Kaposi sarcoma, bone sarcomas, cartilage sarcomas and gastrointestinal stromal tumor (GIST)
Definitive clinical or radiologic evidence of metastatic disease; indeterminant lung nodules less than 8 mm are acceptable
The patient has history of another primary malignancy, with the exception of
- Curatively treated non-melanomatous skin cancer;
- Curatively treated cervical carcinoma in situ;
- Non-metastatic prostate cancer
- Other primary non-hematologic malignancies or solid tumor treated with curative intent, no known active disease, and no treatment administered during the last 3 years prior to registration
The patient has a serious cardiac condition, such as congestive heart failure; New York Heart Association class II/ III/IV heart disease; unstable angina pectoris, cardiac stenting within 6 months of enrollment; myocardial infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed clinically significant; or arrhythmias that are symptomatic or require treatment
Females who are pregnant or breastfeeding
Prior systemic chemotherapy for the study cancer (sarcoma); note that prior chemotherapy for a different cancer is allowable; however, unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of alopecia (grade 2 or 3 toxicities from prior anti-tumor therapy that are considered irreversible [defined as having been present and stable for > 6 months], such as ifosfamide-related proteinuria, may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor)
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
Clinically significant bleeding within 4 weeks of screening, current use of warfarin, factor Xa inhibitors, and direct thrombin inhibitors unless these medications can be safely discontinued 14 days prior to AMG-232 (KRT-232) administration; Note: low molecular weight heparin and prophylactic low dose warfarin are permitted; PT/PTT must meet the inclusion criteria; subjects taking warfarin must have their INR followed closely
History of allergic reactions attributed to compounds of similar chemical or biologic composition to AMG 232 (KRT-232)
All subjects must agree to stop the use of all herbal medicines (e.g., St. John's wort), and supplements, within the 10 days prior to receiving the first dose of AMG 232 (KRT-232), and during the protocol AMG 232 (KRT-232) treatment (weeks 1-5); subjects may renew the use of the above at week 6; standard adult multi-vitamin is allowed
All subjects must agree to stop the use of any known CYP3A4 substrates with narrow therapeutic window (such as alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus, or terfenadine; within the 14 days prior to receiving the first dose of AMG 232 (KRT-232) and during protocol AMG 232 (KRT-232) treatment (weeks 1-5); other medications (such as fentanyl and oxycodone) may be allowed per investigator's assessment/evaluation
All subjects must agree to stop the use of any known CYP2C8 substrates with a narrow therapeutic window within the 14 days prior to receiving the first dose of AMG 232 (KRT-232) and during protocol AMG 232 (KRT-232) treatment (weeks 1-5)
All subjects are required to submit a list of medications consumed within 14 days prior to receiving the first dose of AMG232 (KRT-232) and during the protocol AMG232 (KRT-232) treatment (weeks 1-5)
Patients with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis), therefore could affect the absorption of AMG 232 (KRT-232) at the discretion of treating physician
Patients with active infection requiring intravenous (IV) antibiotics within 2 weeks of registration
Patients with known positive hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B), positive hepatitis total core antibody with negative HBsAG (suggestive of occult hepatitis B), or detectable hepatitis C virus RNA by a polymerase-chain reaction (PCR) assay (indicative of active hepatitis C - screening is generally done by hepatitis C antibody (HepCAb), followed by hepatitis C virus RNA by PCR if HepCAb is positive)
Patients known to be positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have:
- A stable regimen of highly active anti-retroviral therapy (HAART)
- No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based test
- HIV testing is not required
Treatment with medications known to cause corrected QT (QTc) interval prolongation within 7 days of study day 1 is not permitted unless approved by the sponsor; use of ondansetron is permitted for treatment of nausea and vomiting

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Step 2, Group I (navtemadlin, radiation therapy, surgery)	Navtemadlin	Starting with week 2, patients receive navtemadlin as in Step 1 and undergo RT daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
Step 2, Group I (navtemadlin, radiation therapy, surgery)	Radiation Therapy	Starting with week 2, patients receive navtemadlin as in Step 1 and undergo RT daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
Step 2, Group I (navtemadlin, radiation therapy, surgery)	Surgical Procedure	Starting with week 2, patients receive navtemadlin as in Step 1 and undergo RT daily for 5 weeks in the absence of disease progression or unacceptable toxicity, followed by surgery 5-8 weeks after RT completion.
Step 1 (tumor tissue testing, navtemadlin)	Radiation Therapy	Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin 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, Group II (radiation therapy, surgery)	Radiation Therapy	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.
Step 2, Group II (radiation therapy, surgery)	Surgical Procedure	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.
Step 1 (tumor tissue testing, navtemadlin)	Navtemadlin	Patients undergo tumor tissue testing for p53 gene status and receive navtemadlin 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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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

Trial Locations

Locations (53): Logan Health Medical Center
🇺🇸
Kalispell, Montana, United States
CTCA at Western Regional Medical Center
🇺🇸
Goodyear, Arizona, United States
Mayo Clinic Hospital in Arizona
🇺🇸
Phoenix, Arizona, United States
Mayo Clinic in Arizona
🇺🇸
Scottsdale, Arizona, United States
University of Arizona Cancer Center-Orange Grove Campus
🇺🇸
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
🇺🇸
Tucson, Arizona, United States
UCHealth University of Colorado Hospital
🇺🇸
Aurora, Colorado, United States
Poudre Valley Hospital
🇺🇸
Fort Collins, Colorado, United States
Emory University Hospital Midtown
🇺🇸
Atlanta, Georgia, United States
Emory University Hospital/Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
Northside Hospital
🇺🇸
Atlanta, Georgia, United States
CTCA at Southeastern Regional Medical Center
🇺🇸
Newnan, Georgia, United States
Saint Alphonsus Cancer Care Center-Boise
🇺🇸
Boise, Idaho, United States
Northwestern University
🇺🇸
Chicago, Illinois, United States
Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
University of Kansas Cancer Center-Overland Park
🇺🇸
Overland Park, Kansas, United States
The James Graham Brown Cancer Center at University of Louisville
🇺🇸
Louisville, Kentucky, United States
Mayo Clinic in Rochester
🇺🇸
Rochester, Minnesota, United States
Siteman Cancer Center at West County Hospital
🇺🇸
Creve Coeur, Missouri, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Siteman Cancer Center-South County
🇺🇸
Saint Louis, Missouri, United States
Benefis Sletten Cancer Institute
🇺🇸
Great Falls, Montana, United States
Nebraska Methodist Hospital
🇺🇸
Omaha, Nebraska, United States
Rutgers Cancer Institute of New Jersey
🇺🇸
New Brunswick, New Jersey, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸
New York, New York, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Ohio State University Comprehensive Cancer Center
🇺🇸
Columbus, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Thomas Jefferson University Hospital
🇺🇸
Philadelphia, Pennsylvania, United States
Fox Chase Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
Eastern Regional Medical Center
🇺🇸
Philadelphia, Pennsylvania, United States
UPMC-Shadyside Hospital
🇺🇸
Pittsburgh, Pennsylvania, United States
Parkland Memorial Hospital
🇺🇸
Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
Aurora Cancer Care-Southern Lakes VLCC
🇺🇸
Burlington, Wisconsin, United States
Aurora Health Center-Fond du Lac
🇺🇸
Fond Du Lac, Wisconsin, United States
Aurora Health Care Germantown Health Center
🇺🇸
Germantown, Wisconsin, United States
Aurora Cancer Care-Grafton
🇺🇸
Grafton, Wisconsin, United States
Aurora BayCare Medical Center
🇺🇸
Green Bay, Wisconsin, United States
Aurora Cancer Care-Kenosha South
🇺🇸
Kenosha, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸
Madison, Wisconsin, United States
Aurora Bay Area Medical Group-Marinette
🇺🇸
Marinette, Wisconsin, United States
Aurora Cancer Care-Milwaukee
🇺🇸
Milwaukee, Wisconsin, United States
Aurora Saint Luke's Medical Center
🇺🇸
Milwaukee, Wisconsin, United States
Aurora Sinai Medical Center
🇺🇸
Milwaukee, Wisconsin, United States
Vince Lombardi Cancer Clinic - Oshkosh
🇺🇸
Oshkosh, Wisconsin, United States
Aurora Cancer Care-Racine
🇺🇸
Racine, Wisconsin, United States
Vince Lombardi Cancer Clinic-Sheboygan
🇺🇸
Sheboygan, Wisconsin, United States
Aurora Medical Center in Summit
🇺🇸
Summit, Wisconsin, United States
Vince Lombardi Cancer Clinic-Two Rivers
🇺🇸
Two Rivers, Wisconsin, United States
Aurora Cancer Care-Milwaukee West
🇺🇸
Wauwatosa, Wisconsin, United States
Aurora West Allis Medical Center
🇺🇸
West Allis, Wisconsin, United States