A Phase 2 Study of Intravenous AMB-05X in Tenosynovial Giant Cell Tumor Patients

AMB-05X drug substance is a human monoclonal antibody against the colony-stimulating factor 1 receptor (CSF1R).

• AMB-05X (Biological): AMB-05X is a fully human antibody antagonist (immunoglobulin G, type 2 \[IgG2\]) specific to the extracellular domain of human CSF1R

Primary outcomes

• Treatment-emergent Adverse Events (TEAEs) [6 months]: The frequency and severity of reported TEAEs in Subjects with Tenosynovial Giant Cell Tumor (TGCT) receiving Intravenous AMB 05X.

Secondary outcomes

• Overall Tumor Response (Objective Response) Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 [12 weeks]: Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; Per RECIST v1.0 for target lesions and assessed by MRI: A Complete Response (CR) is defined as disappearance of all tumors. A Partial Response (PR) is defined as at least a 30% decrease in the sum of diameters of target tumors from the baseline sum of diameters.
• Overall Response Based on Tumor Volume Score (TVS) [24 weeks or ET visit]: Tumor Volume Score (TVS) calculates tumor volume as a percentage of the estimated volume of the maximally distended synovial cavity or tendon sheath and provides a score in 10% increments. A score of 0 indicates no evidence of tumor; a score of 10 indicates a tumor that is equal in volume to that of a maximally distended synovial cavity or tendon sheath. Complete response (CR): lesion is completely gone; Partial response (PR): >/=50% decrease in TVS relative to Baseline; Progressive disease (PD): >/= 30% increase in TVS relative to the lowest score during the study; Stable disease (SD): does not meet any of the other classifications.
• Mean Change From Baseline Range of Motion (ROM) (Flexion, Knee) Scores [week 12]: Mean Change from Baseline in Range of Motion (ROM) Scores - Flexion (knee only). ROM is assessed by qualified assessors and recorded in degrees. At Baseline, the plane of movement with the smallest (worst) relative ROM was identified; only this plane was used for evaluating change in ROM. Higher scores indicate greater range of motion.
• Mean Change From Baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Score [12 weeks]: Mean change from Baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function score is used to assess physical function. PROMIS is a 10-question patient reported outcome instrument used to assess physical functioning based on use of the upper extremities (dexterity), lower extremities (walking or mobility), and central regions (neck, back) and on instrumental activities of daily living. Five questions address the degree to which the subject's health limits activities, and subjects select a response that ranges from 1-"cannot do" to 5-"not at all". Five additional questions address the degree to which the subject is able to perform certain physical activities, and subjects select a response to each question that ranges from 1 ("cannot do") to 5 ("without any difficulty"). Raw scores are summarized. The score range is 10 to 50, higher scores = worse physical function
• Serum Cmax for AMB-05X at Week 10 Post Dose [10 weeks]: The maximum concentration of AMB-05X in subject serum is measured at week 10 postdose, using sensitive enzyme-linked immunosorbent assay analyses (ELISA).
• Number of Subjects With Anti-Drug Antibodies to AMB-05X at Week 10 [10 weeks]: AMB-05X Anti-drug Antibodies (ADA) in subject serum will be measured from pre-dose samples.
• Mean Change From Baseline in Worst Stiffness Numeric Rating Scale (NRS) Score [12 weeks]: The mean changes from Baseline in the Worst Stiffness Numeric Rating Scale (NRS) score, a Patient-Reported Outcome (PRO) Measurement. The Worst Stiffness NRS is a single-item instrument designed to assess "worst" stiffness at the site of the tumor in the last 24 hours. The instrument uses an 11-point numeric rating scale that ranges from 0 ("no stiffness") to 10 ("stiffness as bad as you can imagine"). Higher scores indicate worse stiffness.
• Brief Pain Inventory Pain Severity Domain Score [12 weeks]: The mean changes from Baseline in Brief Pain Inventory (BPI) Pain Severity Domain. (Score of 0-10, where a negative score from baseline indicates a better BPI score, less severe pain) Brief Pain Inventory (BPI) is a self-administered questionnaire used to evaluate the severity of a subject's pain and the impact of this pain on the subject's daily functioning. For the Pain Severity domain the subject is asked to rate their worst, least, average, and current pain intensity, and list current treatments and their perceived effectiveness on a scale from 0 to 10, where higher scores mean more severe pain. All of the 0-10 scores are averaged to obtain the total Domain (subscale) Score.
• Mean Change From Baseline in Brief Pain Inventory Severity Interference [12 weeks]: The mean changes from Baseline in Brief Pain Inventory (BPI) Severity Interference domain. The BPI Short Form is a patient-reported outcome instrument used to evaluate the severity of a subject's pain and the impact of this pain on the subject's daily functioning. For this domain, the subject is asked to rate their worst, least, average, and current pain intensity, list current treatments and their perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life on a scale from 0 to 10, where higher scores mean more pain interference. The reported score is the mean of the seven interference items. Higher scores indicate greater levels of pain.
• Worst Pain Numeric Rating Scale Score [12 weeks]: Mean change from Baseline in Worst Pain Numeric Rating Scale score. The Worst Pain Numeric Rating Scale is an item in the BPI that assesses a subject's "worst" pain in the last 24 hours. The 11-point Numeric Rating Scale for this item ranges from 0 ("no pain") to 10 ("pain as bad as you can imagine"). Higher scores indicate greater level of pain.
• EuroQol 5 Dimension 5 Level Health Assessment [12 weeks]: Mean change from Baseline in the EuroQol 5 Dimension 5 Level (EQ-5D-5L) assessment Scale Score (5-25). This instrument is a self-report survey that measures quality of life across 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is scored on a 5-level severity ranking that ranges from "no problems" through "extreme problems". Higher scores indicate a lower quality of life.
• Colony-stimulating Factor 1 Levels [10 weeks]: Serum colony-stimulating factor-1 (CSF-1) levels are measured in patient/subject serum. Samples were collected for measurement of CSF-1 at least once at specified visits.
• Mean Change From Baseline Rnge of Motion (Flexion, Ankle) Scores [week 12]: Mean Change from Baseline in Range of Motion (ROM) Scores - Flexion (Ankle only). ROM is assessed by qualified assessors and recorded in degrees. At Baseline, the plane of movement with the smallest (worst) relative ROM was to be identified; only this plane was used for evaluating change in ROM. Higher scores indicate greater range of motion.
• Serum AMB-05X-Binding Anti-drug Antibody (ADA) Levels [Week 12]: Series analysis for anti-drug antibody detection and titer

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Subject ≥ 18 years
2. A confirmed diagnosis of TGCT
3. Measurable disease based on RECIST v1.1
4. Symptomatic disease
5. Stable prescription of analgesic regimen
6. Agrees to follow contraception guidelines
7. Adequate hematologic, hepatic, and renal function, at Screening
8. Willing and able to complete self-assessment instruments throughout the study

Exclusion Criteria:

1. Prior investigational drug use within 4 weeks or 5 half-lives of Baseline
2. Current or prior radiotherapy within 3 months before Baseline
3. Current or prior active cancer within 3 years before Baseline that requires/required therapy (eg, surgery, chemotherapy, or radiation therapy)
4. Known metastatic TGCT or malignant transformation of diffuse-type TGCT
5. Hepatitis C virus (HCV) or hepatitis B virus (HBV) or known active or chronic infection with human immuno deficiency virus (HIV)
6. Known active tuberculosis (TB)
7. Significant concomitant arthropathy in the affected joint, serious illness, uncontrolled infection, or a medical or psychiatric history
8. Women who are pregnant or breastfeeding
9. Screening Fridericia-corrected QT interval(QTcF) ≥450ms (men) or ≥470ms (women)
10. MRI contraindications (eg, pacemaker, loose metallic implants)
11. History of hypersensitivity to any ingredient in the study drug
12. History of drug or alcohol abuse within 3 months before Baseline
13. Has any other severe acute or chronic medical or psychiatric condition or clinically significant laboratory abnormality that may increase the risk associated with study participation/treatment, interfere with interpretation of study results, or, in the Investigator's opinion, make the subject inappropriate for this study
14. A person who is held in detention as the result of a judicial or official decision or who is in a subordinate relationship to the Sponsor or Investigator
15. A subject who, in the opinion of the Investigator, should not participate in the study for any reason, including if there is a question about the subject's ability to comply with study requirements

Participant flow

Outcome results

• Treatment-emergent Adverse Events (TEAEs) (Primary), Count of participants, Participants: Cohort A: Subjects With TGCT 4
• Overall Tumor Response (Objective Response) Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 (Secondary), Count of participants, Participants: Cohort A: Subjects With TGCT 0
• Overall Response Based on Tumor Volume Score (TVS) (Secondary), Count of participants, Participants: Cohort A: Subjects With TGCT 0
• Mean Change From Baseline Range of Motion (ROM) (Flexion, Knee) Scores (Secondary), Count of participants, Participants: Cohort A: Subjects With TGCT 1
• Mean Change From Baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Score (Secondary), Mean, score on a scale: Cohort A: Subjects With TGCT 0 +/- 2.65
• Serum Cmax for AMB-05X at Week 10 Post Dose (Secondary), Mean, ng/mL: Cohort A: Subjects With TGCT 54,457 +/- 30,356
• Number of Subjects With Anti-Drug Antibodies to AMB-05X at Week 10 (Secondary), Count of participants, Participants: Subjects With Tenosynovial Giant Cell Tumor 1
• Mean Change From Baseline in Worst Stiffness Numeric Rating Scale (NRS) Score (Secondary), Mean, score on a scale: Cohort A: Subjects With TGCT -2.7 +/- 2.52
• Brief Pain Inventory Pain Severity Domain Score (Secondary), Mean, score on a scale: Cohort A: Subjects With TGCT -0.83 +/- 1.665
• Mean Change From Baseline in Brief Pain Inventory Severity Interference (Secondary), Mean, score on a scale: Cohort A: Subjects With TGCT 0.81 +/- 1.528
• Worst Pain Numeric Rating Scale Score (Secondary), Mean, score on a scale: Cohort A: Subjects With TGCT -0.3 +/- 1.53
• EuroQol 5 Dimension 5 Level Health Assessment (Secondary), Mean, score on a scale: Cohort A: Subjects With TGCT -0.3 +/- 0.58
• Colony-stimulating Factor 1 Levels (Secondary), Mean, pg/mL: Cohort A: Subjects With TGCT 1216 +/- 372
• Mean Change From Baseline Rnge of Motion (Flexion, Ankle) Scores (Secondary)
• Serum AMB-05X-Binding Anti-drug Antibody (ADA) Levels (Secondary), Count of participants, Participants: Subjects With Tenosynovial Giant Cell Tumor 3

Adverse events

Time frame: 6 months

Other adverse events by term

Limitations and caveats: A decision was made in November 2021 to stop further enrollment into the study to allow development to focus on AMB-05X intra-articular administration for TGCT. A total of 4 subjects had been enrolled into the study at the time the decision to cease further enrollment was made, limiting the ability to interpret the resulting data.

• Study Protocol and Statistical Analysis Plan (PDF, 2021-08-18)

• Dorothy Nguyen, MD, Study chair, AmMax Bio, Inc.