Clinical trial NCT03217266: Navtemadlin and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma
Official title: A Phase Ib Trial of Neoadjuvant AMG 232 (KRT-232) Concurrent With Preoperative Radiotherapy in Wild-Type P53 Soft Tissue Sarcoma (STS)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Resectable Soft Tissue Sarcoma
Soft Tissue Sarcoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: NRG Oncology
First posted: 2017-07-14
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) / Recommended Phase 2 Dosage for Each Cohort
timeFrame: Baseline to end of navtemadlin + 4 weeks (approximately 10 weeks total)
measure: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)
timeFrame: Baseline to end of navtemadlin + 4 weeks (approximately 10 weeks total)
Secondary outcomes:
measure: Percent of Necrosis in Final Surgical Resection Specimen
timeFrame: At time of surgery (approximately 11 to 14 weeks)
measure: Number of Participants With Pathologic Complete Response (PCR) in Final Surgical Resection Specimen
timeFrame: At time of surgery (approximately 11 to 14 weeks)
measure: Number of Participants With Local Failure
timeFrame: Baseline to the date of failure or last known follow-up, up to 2.5 years from end of RT (six weeks).
measure: Number of Participants With Disease or Death From Any Cause
timeFrame: Baseline to the date of disease, death, or last known follow-up, up to 2.5 years from end of RT (six weeks).
measure: Number of Participants Who Died
timeFrame: Baseline to the date of death or last known follow-up, up to 2.5 years from end of RT (six weeks).
measure: Serial Serum Macrophage Inhibitory Cytokine-1 Levels
timeFrame: Up to 2.5 years
measure: Navtemadlin Exposure-response Relationships
timeFrame: Up to 2.5 years
Other outcomes:
measure: Tumor Volume Changes
timeFrame: Up to 2.5 years
measure: Clinical Outcomes by Genomic Biomarkers
timeFrame: Up to 2.5 years
measure: mdm2/4 Expression
timeFrame: Up to 2.5 years
measure: Tumor Genetic Mutations in Deoxyribonucleic Acid Ribonucleic Acid Isolated From Exosomes
timeFrame: Up to 2.5 years
Locations:
city: Goodyear
country: United States
facility: CTCA at Western Regional Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Hospital in Arizona
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center-Orange Grove Campus
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center-North Campus
state: Arizona
city: Aurora
country: United States
facility: UCHealth University of Colorado Hospital
state: Colorado
city: Fort Collins
country: United States
facility: Poudre Valley Hospital
state: Colorado
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Newnan
country: United States
facility: CTCA at Southeastern Regional Medical Center
state: Georgia
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Overland Park
country: United States
facility: University of Kansas Cancer Center-Overland Park
state: Kansas
city: Louisville
country: United States
facility: The James Graham Brown Cancer Center at University of Louisville
state: Kentucky
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Great Falls
country: United States
facility: Benefis Sletten Cancer Institute
state: Montana
city: Kalispell
country: United States
facility: Logan Health Medical Center
state: Montana
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Eastern Regional Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC-Shadyside Hospital
state: Pennsylvania
city: Dallas
country: United States
facility: Parkland Memorial Hospital
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Burlington
country: United States
facility: Aurora Cancer Care-Southern Lakes VLCC
state: Wisconsin
city: Fond Du Lac
country: United States
facility: Aurora Health Center-Fond du Lac
state: Wisconsin
city: Germantown
country: United States
facility: Aurora Health Care Germantown Health Center
state: Wisconsin
city: Grafton
country: United States
facility: Aurora Cancer Care-Grafton
state: Wisconsin
city: Green Bay
country: United States
facility: Aurora BayCare Medical Center
state: Wisconsin
city: Kenosha
country: United States
facility: Aurora Cancer Care-Kenosha South
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - University Hospital
state: Wisconsin
city: Marinette
country: United States
facility: Aurora Bay Area Medical Group-Marinette
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora Cancer Care-Milwaukee
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora Saint Luke's Medical Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora Sinai Medical Center
state: Wisconsin
city: Oshkosh
country: United States
facility: Vince Lombardi Cancer Clinic - Oshkosh
state: Wisconsin
city: Racine
country: United States
facility: Aurora Cancer Care-Racine
state: Wisconsin
city: Sheboygan
country: United States
facility: Vince Lombardi Cancer Clinic-Sheboygan
state: Wisconsin
city: Summit
country: United States
facility: Aurora Medical Center in Summit
state: Wisconsin
city: Two Rivers
country: United States
facility: Vince Lombardi Cancer Clinic-Two Rivers
state: Wisconsin
city: Wauwatosa
country: United States
facility: Aurora Cancer Care-Milwaukee West
state: Wisconsin
city: West Allis
country: United States
facility: Aurora West Allis Medical Center
state: Wisconsin
Study officials:
affiliation: NRG Oncology
name: Meng X Welliver
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vatner R, James CD, Sathiaseelan V, Bondra KM, Kalapurakal JA, Houghton PJ. Radiation therapy and molecular-targeted agents in preclinical testing for immunotherapy, brain tumors, and sarcomas: Opportunities and challenges. Pediatr Blood Cancer. 2021 May;68 Suppl 2:e28439. doi: 10.1002/pbc.28439. Epub 2020 Aug 22.
citation: Elzanowska J, Semira C, Costa-Silva B. DNA in extracellular vesicles: biological and clinical aspects. Mol Oncol. 2021 Jun;15(6):1701-1714. doi: 10.1002/1878-0261.12777. Epub 2020 Aug 19.