A multicenter, randomized, double-blind phase III study to evaluate the safety and efficacy of Emactuzumab compared to placebo in patients with tenosynovial giant cell tumor (Short title: TANGENT)

Austria, Belgium, Canada, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, Switzerland, United Kingdom, United States (ICTRP)

ICTRP Trial ID
EUCTR2021-001716-29 (ICTRP)

Official title (approved by ethics committee)
A Phase III, Multicentre, Randomised, Double-Blind Study to Assess the Safety and Efficacy of Emactuzumab vs. Placebo in Subjects with Tenosynovial Giant Cell Tumour (BASEC)

Academic title
A Phase III, Multicentre, Randomised, Double-Blind Study to Assess the Safety and Efficacy ofEmactuzumab vs. Placebo in Subjects with Tenosynovial Giant Cell Tumour. - TANGENT (ICTRP)

Public title
A Trial to Assess the Safety and Efficacy of Emactuzumab versus Placebo in Patients with Giant Cell Tumours. (ICTRP)

Disease under investigation
Tenosynovial Giant Cell Tumour
MedDRA version: 21.1Level: LLTClassification code 10025564Term: Malignant giant cell tumorSystem Organ Class: 100000004864;Therapeutic area: Diseases [C] - Cancer [C04] (ICTRP)

Intervention under investigation

Product Name: Emactuzumab (RO5509554)
Product Code: RO5509554
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: EMACTUZUMAB
Current Sponsor code: RO5509554, RG7155
Other descriptive name: RO5509554, RG7155
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Concentrate and solvent for solution for infusion
Route of administration of the placebo: Intravenous use

(ICTRP)

Type of trial
Interventional clinical trial of medicinal product (ICTRP)

Trial design
Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2 (ICTRP)

Inclusion/Exclusion criteria
Gender:
Female: yes
Male: yes

Inclusion criteria:
1. Written informed consent.
2. 2.Biopsy-confirmed (standard of care diagnosis history) local or diffuse TGCT where surgical resection would be associated with predicted worsening functional limitations due to surgical damage to the joint and adjacent soft tissues, and/or subject presents with an anticipated high risk of early recurrence as determined by a multidisciplinary tumour board or equivalent*, or any other morbidity associated with the surgery, and/or surgical treatment is not expected to improve the clinical outcomes of the subject.
*The multidisciplinary tumour board or equivalent must comprise at least 2 individuals: the Investigator plus at least one other qualified physician (orthopaedic surgeon or medical oncologist) not involved in this study
3. Measurable disease: longest diameter =20 mm.
4. Age >12 years.
5. Adequate organ and bone marrow function: haemoglobin (Hb) >10.0 g/dL,
neutrophils >1.5 ? 109/L and platelets >100 ? 109/L.
6. Minimum mean score of 4 on NRS for Worst Pain during 7 days prior to randomization,
based upon a minimum of 4 days of completed diary data.
7. Minimum mean score of 4 on NRS for Worst Stiffness during 7 days prior to
randomization, based upon a minimum of 4 days of completed diary data.
8. Women of childbearing potential (WOCBP) must have a negative urine and serum pregnancy test prior to starting treatment. WOCBP must agree to use a highly effective method of contraception throughout the treatment period and for 7 months after discontinuation of treatment. Acceptable methods of contraception according to protocol description.
9. For Open-Label Phase ONLY:
Subjects must either:
-Have responded based on RECIST v1.1 (CR or PR) to initial treatment with emactuzumab during the Double-Blind Phase and then progressed (objective progressive disease on imaging) within 9-18 months of initial treatment on D 1 (Visit 1) with a minimum 6-month washout period between treatments; or
-Have received placebo and completed the 6-month visit on D 181/Visit 10
(3 months treatment and 3 months observation) of the Double-Blind Phase and
have not completed more than 18 months of the study since initial treatment on D1 (Visit1).
Are the trial subjects under 18? yes
Number of subjects for this age range: 3
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 150
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 7
(ICTRP)

Exclusion criteria:
1. Pregnant or breast feeding.
2. Medical conditions, including auto-immune, requiring systemic immunosuppression. Any
systemic treatment for these conditions (eg, glucocorticoids) is not allowed within
4 weeks of Screening and during the study. All Lupus Erythematosus are excluded
irrespective of treatment.
3. Metastatic TGCT.
4. TGCT currently affecting multiple joints.
5. Pexidartinib therapy within 3 months of Screening.
6. Nilotinib, imatinib; other chemotherapy, radiotherapy, or investigational therapy within 4
weeks of Screening.
7. Unresolved clinically significant toxicity from a previous treatment or any history of
serious liver toxicity.
8. Current or chronic history of liver disease. This includes, but is not limited to, hepatitis
virus infections, drug- or alcohol-related liver disease, nonalcoholic steatohepatitis,
autoimmune hepatitis, haemochromatosis, Wilson?s disease, a-1 antitrypsin deficiency,
primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease
which in the opinion of the Investigator is considered clinically significant.
9. Renal function: creatinine clearance <60 mL/min (Cockcroft-Gault formula).
10. Liver function: ALT >3.0 ? ULN; OR total bilirubin >1.5 ? ULN.
11. Within 6 months of baseline has experienced: clinically significant myocardial infarction,
severe/unstable angina pectoris, congestive heart failure New York Heart Association
(NYHA) Class III or IV, or pulmonary disease (NYHA Criteria 1994).
12. Clinically significant active infection requiring systemic antibiotic treatment.
Rescreening may occur any time after 7 days post completion of treatment.
13. Systemic antiretroviral therapy within 3 months of baseline.
14. Other active cancer that requires concurrent treatment or history of malignancy other than
TGCT, unless there is the expectation that the malignancy has been cured, and tumor
specific treatment for the malignancy has not been administered within the previous
5 years.
15. Planned surgery during the course of the study with the exception of dental treatment.
16. Inability to comply with the study procedures.
17. For the Double-Blind Phase ONLY:
Previous exposure to emactuzumab and/or neutralizing antibodies.


Primary and secondary end points
Main Objective: To estimate the treatment effect of emactuzumab on objective response rate (ORR) by 6 months from initiation of therapy in the blinded phase compared to placebo.;Secondary Objective: -To estimate:
The effect of emactuzumab on clinical outcome assessments (COAs) for:

o Physical functioning
o Range of motion (ROM)
o Pain
o Stiffness
o Patient Global Impressions (PGIs)
o QoL

-Further antitumour activity of emactuzumab in TGCT compared to placebo.

-Surgical Intervention Rate.

-The Safety Objective of this study is to monitor subject wellbeing and assess treatment tolerability .

-To assess the health economic impact of treatment with emactuzumab.

-To further characterize the pharmacokinetic (PK) profile of emactuzumab.;Primary end point(s): The primary efficacy objective of this study is to estimate the treatment effect of emactuzumab on objective response rate (ORR) by 6 months from initiation of therapy in the blinded phase compared to placebo;Timepoint(s) of evaluation of this end point: ORR by 6 months from initiation of therapy based on independent, blinded central review (ICTRP)

Secondary end point(s): Change in Patient-Reported Outcomes Measurement Information System-Physical Function
(PROMIS-PF) TGCT from baseline to 6 months.

Other secondary endpoints:
-Change in PROMIS-PF TGCT from baseline over time.
-Physician/Healthcare Professional (HCP)-Reported Joint Mobility Score by goniometry from baseline over time.
-Change in Worst Pain Numerical Rating Scale (NRS) from baseline over time.
-Change in Short Form 12-Item Survey version 2 (SF-12 v2) from baseline over time.
-Change in Worst Stiffness NRS from baseline over time.
-PGI of change and severity over time.
-Change in EuroQol 5-dimension, 5-level questionnaire (EQ-5D-5L) from baseline over time.
-Duration of response (DoR) as measured by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 based on independent, blinded central review.
-Disease control rate (DCR) as measured by RECIST v1.1 based on independent, blinded central review
-Time to progression as measured by RECIST v1.1 based on independent, blinded central review.
-Change in Tumour volume score (TVS) from baseline over time.
-Surgical intervention rate, defined as the number of subjects who undergo surgery for TGCT during the study.
-AEs.
-Deaths.
-Any laboratory abnormalities.;Timepoint(s) of evaluation of this end point: From baseline over time. (ICTRP)

Registration date
28.06.2022 (ICTRP)

Incorporation of the first participant
08.09.2022 (ICTRP)

Secondary sponsors
not available

Additional contacts
Rowena Abbey, Rowena.Abbey@synoxtherapeutics.com, 447789626678, SynOx Therapeutics Ltd (ICTRP)

Secondary trial IDs
SNX-301-020, 153633, 2021-001716-29-BE (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-001716-29 (ICTRP)