| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable locally-advanced or metastatic synovial sarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Unresectable locally-advanced or metastatic synovial sarcoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Evaluate the efficacy of CMB305 versus placebo using:
o Progression-free survival (PFS), by investigator assessment, using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
o Overall survival (OS) |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the efficacy of CMB305 versus placebo using:
o Time- to-next treatment (TTNT)
o Distant metastasis-free survival (DMFS)
o Objective response rate (ORR) (defined by RECIST v1.1)
• Evaluate the safety and tolerability of CMB305 versus placebo
• Evaluate subject quality of life (QoL) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria:
1.Have documented histologic diagnosis of synovial sarcoma (may be confirmed by the presence of t(X;18) (p11:q11) translocation or B cell lymphoma 6 corepressor [BCOR] rearrangement) and have disease that is unresectable locally-advanced or metastatic prior to the start of first-line systemic anti-cancer therapy. Unresectable is defined as having evidence of positive surgical margins after resection of primary disease or a documented surgical consultation with assessment of an inability of resection to provide clear margins.
2.Have IHC test results from tumor biopsy for NY ESO 1 that are positive (≥1% expression).
3.At the time of Pre screening, subjects must be receiving a first line anthracycline or ifosfamide-containing systemic anti-cancer therapy regimen (single agent ifosfamide, single agent anthracycline, combination anthracycline plus ifosfamide, or combination anthracycline plus olaratumab). Subjects must have received at least 4 cycles but no more than 8 cycles of therapy (or no more than 180 days of systemic anti-cancer therapy). Subjects who have received local regional therapy (surgical resection, radiotherapy, radiofrequency ablation, or cryotherapy) are eligible if they meet the following:
a.Subjects whose disease converted to operable after completion of first-line chemotherapy are eligible, if local regional therapy (surgical resection, radiotherapy, radiofrequency ablation or cryotherapy) is completed within the 180-day period from the date of the first dose of first-line systemic anti-cancer therapy. Please note that an extension of this 180-day may be allowed per Section 3.3 of the protocol.
b.Subjects whose disease remains inoperable after completion are eligible, if radiotherapy is completed within the 180-day period from the date of the first dose of first-line systemic anti-cancer therapy and there is no evidence of progressive disease prior to initiation of radiotherapy. Please note that an extension of this 180-day period may be allowed per Section 3.3 of the protocol.
c.Subjects who have PD ≤6 months after date of last dose of adjuvant/neoadjuvant systemic anti-cancer therapy or date of last day of local regional therapy are not eligible.
4.Must have documentation of no evidence of disease progression of the tumor during or after completion of first line systemic anti-cancer therapy as determined by the investigator using RECIST v1.1 guidelines. Subjects who have a tumor response of SD with evidence of ≥15% to 20% increase in tumor burden will be submitted for Central Review to adjudicate the investigator’s assessment of tumor response prior to randomization. Subjects with NED are eligible.
5.Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6.Age ≥12 years.
7.Have a life expectancy of at least 6 months, as determined by the investigator.
8.If a female of child-bearing potential (FCBP), willing to undergo pregnancy testing and agree to use at least 1 highly-effective (e.g., combined [estrogen and progesterone containing] oral hormonal contraception, intrauterine device, vasectomy, or sexual abstinence) or 2 effective contraceptive methods (e.g., condom, diaphragm, oral progesterone only contraception) during the dosing period and for 1 month (which is the duration of a menstruation cycle) after administration of the last dose of CMB305. More stringent contraception criteria should be followed if requested by local regulatory authorities.
9.If male and sexually active with a FCBP, must be surgically sterile (i.e., vasectomy) or agree to use highly effective contraception, such as latex condom, during the dosing period and for 3 months (which is the duration of a sperm cycle) after administration of the last dose of CMB305. More stringent contraception criteria should be followed if requested by local regulatory authorities.
10.Have recovered from the toxic effects (except alopecia) to grade 2 or better from systemic anti cancer therapy according the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 (or newer).
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|
| E.4 | Principal exclusion criteria |
1. Have received the last dose of first-line systemic anti-cancer therapy or date of most recent local regional therapy >28 days prior to Day 1.
2. Have received prior anti-NY-ESO-1 therapy.
3. Have received first-line systemic anti-cancer therapy other than an anthracycline-containing or ifosfamide-containing regimen (single agent anthracycline, single agent ifosfamide, combination anthracycline plus ifosfamide, or combination anthracycline plus olaratumab).
4. Have received treatment with systemic immunomodulatory agents (including, but not limited to, interleukin-2) within 28 days prior to administration of the first dose of CMB305 (i.e., Day 1) or 5 half-lives of the drug, whichever occurs sooner.
5. Have significant immunosuppression from:
a. Concurrent, recent (≤21 days prior to administration of the first CMB305 dose [i.e., Day 1]), or anticipated need for chronic treatment with systemic immunosuppressive dose of corticosteroids (the use of physiologic doses of corticosteroids may be approved after consultation with the sponsor).
b. Other immunosuppressive medications (≤21 days prior to administration of the first CMB305 dose [i.e., Day 1]) including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents or conditions such as common variable hypogammaglobinemia.
6. Have psychiatric, other medical illness, or any other condition that, in the opinion of the investigator, prevents compliance with the study procedures or the ability to provide valid informed consent (or assent for subjects 12 to <18 years of age).
7. Have a history of uncontrolled autoimmune disease.
8. Have significant electrocardiogram (ECG) finding or cardiovascular disease, such as New York Heart Association cardiac disease (>Class II), myocardial infarction within the previous 3 months before administration of the first dose of CMB305 (i.e., Day 1), unstable arrhythmias, or unstable angina.
9. Have inadequate organ function as evidenced by:
a. Marrow:
i. Absolute neutrophil count (ANC) ≤1000/mm3
ii. Platelets <75,000/mm3
iii. Hemoglobin (Hgb) <8 g/dL
iv. Lymphocytes ≤800/mm3.
b. Hepatic:
i (ALT) or (AST) >3.0× the upper limit of normal (ULN) for subjects without liver metastases or ≥5× ULN for subjects with liver metastases
ii. Total serum bilirubin >1.5× ULN (or direct bilirubin ≥1.5 ULN for subjects with total bilirubin levels <1.5× ULN). Subjects with Gilbert’s disease may be included if their total bilirubin is <3.0 mg/dL).
c. Renal:
i. Creatinine clearance <0.5 x LLN.
d. For subjects not using blood thinners:
i. Prothrombin time (PT) >1.5× ULN or international normalized ratio (INR) >1.5× ULN
ii. Partial thromboplastin time (PTT) >1.5× ULN
iii. Subjects using blood thinners must be able to modify their normal dosing regimen to allow for injections of investigational product.
10. History of other cancer within 3 years (except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, localized prostate cancer treated with curative intent, ductal carcinoma in situ treated surgically with curative intent, or other cancers with a similar outcome).
11. Evidence of active tuberculosis or recent (<1 week prior to first scheduled dosing on Day 1) clinically-significant infection requiring systemic therapy. (Prophylactic antibiotics [e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease] are permitted.)
12. Evidence of active (HepB), (HepC), or (HIV) infection:
a. Active HepB is defined as having a positive HepB surface antigen (HBsAg) test result at Screening.
b. Subjects with past/resolved HepB infection (defined as having a negative HBsAg test and a positive antibody to HepB core antigen [anti-HBc] antibody test) are eligible. HepB viral DNA results must be negative in these subjects prior to the first scheduled dosing on Day 1.
c. Subjects with test results positive for HepC antibody are eligible only if polymerase chain reaction (PCR) testing is negative for HepC viral RNA.
d. Subjects who are HIV positive.
13. Have had live, attenuated vaccine administered within 28 days prior to the first scheduled dosing on Day 1 or anticipate that such a live, attenuated vaccine will be required during the study.
14. Have a history of brain metastasis.
15. Have received cancer therapies, including chemotherapy, radiation, biologic or kinase inhibitors, granulocyte colony-stimulating factor (G-CSF), or granulocyte-macrophage colony stimulating factor (GM-CSF) within 3 weeks prior to the first scheduled CMB305 dosing.
16. A FCBP who is pregnant, is planning to become pregnant, or is breast feeding; or a male who is sexually active with a FCBP who is planning to become pregnant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Assessments:
• PFS, by investigator assessment, using RECIST v1.1
• OS |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The 2 primary efficacy endpoints of PFS and OS will be compared between CMB305 and placebo. OS is defined as the time from randomization to the date of death. PFS by investigator’s assessment is defined as the time from randomization to the investigator-determined (using RECIST v1.1) date of disease progression or death.
The study completion is 5 years |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Assessments:
• TTNT
• DMFS
• ORR (defined by RECIST v1.1)
• Safety and tolerability
• QoL evaluated using the EuroQol 5-Dimension 5 Level (EQ-5D-5L) for subjects ≥18 years of
age or using the EuroQol 5-Dimension Youth (EQ-5D-Y) for subjects 12 to <18 years of age |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary efficacy endpoints of TTNT, DMFS, ORR, and QoL using the EQ-5D-5L or EQ-5D-Y will be compared between treatment arms.
The secondary efficacy endpoints will only be evaluated if at least 1 of the 2 primary efficacy endpoints demonstrate superiority for CMB305 over placebo. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| Hong Kong |
| Italy |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Singapore |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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