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Sarcoma, SynovialPhase 1SYNFRIZZNCT01469975

First in Man Study Investigating the Biodistribution, the Safety and Optimal Recommended Dose of a New Radiolabelled Monoclonal Antibody Targeting Frizzled Homolog 10

A Phase 1 study testing OTSA101-DTPA-90Y level 1, OTSA101-DTPA-90Y level 2 and OTSA101-DTPA-90Y level 3 in people with Sarcoma, Synovial, run by Centre Leon Berard at 1 site in France.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial summary

Advanced synovial sarcoma represents an unmet medical need. The gene encoding frizzled homologue 10 (FZD10), a 7-transmenbrane receptor, member of the Wnt signalling receptor family, is overexpressed in SS and is undetectable in normal human tissues except placenta. OncoTherapy Science Inc. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Sarcoma, Synovial
What is being tested?
OTSA101-DTPA-90Y level 1, OTSA101-DTPA-90Y level 2 and OTSA101-DTPA-90Y level 3
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
1 siteFrance
Study dates
Dec 2011to 30 Jun 2015
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female patients, age ≥ 18 years.
  • Histologically confirmed progressive synovial sarcoma with a minimal total tumor volume of 65mL at the time of inclusion.
  • Frozen or paraffin-embedded tumor samples for immunohistochemical analysis are mandatory for registration in this study.
  • Patients with doxorubicin- and ifosfamide-resistant synovial sarcoma (defined as patients with progression under doxorubicin and ifosfamide treatments or with rapid progression (i.e. within 4 months) after the last dose of doxorubicin and ifosfamide, or patients previously treated with doxorubicin and ifosfamide and with disease progression on another regimen of chemotherapy for advanced disease).
  • Patients must have disease not amenable to surgery, radiation or combined modality treatment with curative intent.
  • At least one measurable site of disease as defined by RECIST criteria 1.1.
Show all 17Show fewer
  • ECOG performance status of 0, 1, 2.
  • Life expectancy ≥ 3 months.
  • Left Ventricular Ejection Fraction (LVEF)> 50% as assessed by MUGA scan or ECHO at screening.
  • Normal pulmonary function with Force Vital Capacity (FVC) of at least 60% and DLCO of at least 50%.
  • Adequate bone marrow, liver and renal function including the following:
  • Absolute neutrophil count ≥ 1.5 G/L, platelet count ≥ 100 G/L, and hemoglobin ≥ 10 g/dL)
  • AST/ALT ≤ 3 x upper limit of normal (ULN) (or ≤ 5.0 x ULN if liver metastasis) and total bilirubin ≤ 1.5 x ULN (≤ 2.5 x ULN if liver metastases),
  • Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min according to Cockroft formula.
  • Adequate contraceptive methods for the whole duration of the study and for up to 12 months after the last study drug administration.
  • Mandatory affiliation with a health insurance company.
  • Patients must provide written informed consent before any study specific procedures or assessments, and must be willing to comply with follow up assessments and procedures.

Who cannot join

  • Chemotherapy within the last 2 weeks before inclusion; radiotherapy, or any other investigational agent within 14 days or 5 half-lives, whichever is longer prior to the first dose of study drug.
  • Positive human anti-mouse antibody (HAMA) or human anti-chimeric antibody (HACA) response. HAMA/HACA assays will be performed only for patients previously treated by monoclonal antibodies.
  • Uncontrolled arterial hypertension: systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or both despite appropriate therapy.
  • Patients with brain metastases.
  • Previous history of high-dose chemotherapy with stem cell rescue.
  • Chronic use of immunosuppressive drugs such as systemic corticosteroids.
Show all 13Show fewer
  • Previous therapy with monoclonal antibodies within 4 months before study entry.
  • Clinically significant abnormal ECG (i.e. > grade 1) at inclusion.
  • Prior history of other malignancies other than synovial sarcoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the subjects has been free of the disease for at least 3 years.
  • No resolution of all specific toxicities (excluding alopecia) related to any prior anti-cancer therapy to Grade ≤ 1 according to the NCI CTCAE v4.
  • Known immediate or delayed hypersensitivity reaction to 111In, 90Y, DTPA or any excipients of the investigational product.
  • Psychological, familial, sociological, or geographical conditions that would limit compliance with study protocol requirements.
  • Pregnant and breastfeeding women are ineligible.

Trial locations and contacts

1 site in 1 country.

France1 site

  • Centre Léon Bérard

    Lyon, 69373

Other trials in France

About this study

Official title: First in Man Study Investigating the Biodistribution, the Safety and Optimal Recommended Dose of a New Radiolabelled Monoclonal Antibody Targeting Frizzled Homolog 10 (FZD10) in Patients With Relapsed or Refractory Non Resectable Synovial Sarcomas

Advanced synovial sarcoma represents an unmet medical need. The gene encoding frizzled homologue 10 (FZD10), a 7-transmenbrane receptor, member of the Wnt signalling receptor family, is overexpressed in SS and is undetectable in normal human tissues except placenta.

OncoTherapy Science Inc. has developed a chimeric humanized monoclonal antibody (mAb) against FZD10, named OTSA101. Non-radiolabeled OTSA101 antibody has only weak antagonistic activity on SS cell growth. However, Yttrium 90-radiolabeled OTSA101 (OTSA101-DTPA-90Y) showed significant antitumor activity following a single intravenous injection in mouse xenograft model.

Read more

This first in man clinical trial (Phase I) in relapsing SS patients resistant to Doxorubicin and ifosfamide will be divided in 2 parts.

In Part 1 (imaging part using OTSA101 radiolabelled with Indium 111 [111In]), the biodistribution and tumor uptake of OTSA101-DTPA-111In will be followed using 111In as radiotracer.

In Part 2 (therapeutic part with OTSA101 radiolabelled with Yttrium 90 [90Y]), the safety and PK profiles of OTSA101-DTPA-90Y will be determined and preliminary efficacy data will be collected.

This first in Man study should allow defining the optimal recommended dose of OTSA101-DTPA-90Y.

Patients will be followed during 1 year.

Read the detailed description

PART 1: Imaging with OTSA101 DTPA-111In OTSA101-DTPA-111In (1.5mg OTSA101-DTPA radiolabeled with 185 MBq of 11In) will be administered intravenously (IV) as a single injection on Day -28 (D-28). Patients will undergo serial anterior-posterior gamma scans and single photon emission computed tomography (SPECT/CT) at 1, 5, 24, 48, 72, 144 hours post-dosing to estimate absorbed radiation doses to tumor, to normal organs (i.e., liver, lung, kidney, and bone marrow), and whole body in order to determine OTSA101-DTPA-111In tumor uptake (ID%/g [% of injected dose (ID) per gram of tumor]) and biodistribution (ratio tumor/normal tissue of estimated radiation-absorbed dose). PK sampling will be performed at the same time points with additional sampling at D-14 and D0.

A Steering Committee meeting is planned at the end of PART 1 for each patient. The Steering Committee will evaluate on a case by case basis at Day -7 for each patient if he/she can proceed to the therapeutic part based on tumor targeting, biodistribution, safety and clinical assessments:

  • Patients with expected biodistribution and tumor uptake, no safety concerns and no overt signs of disease progression will proceed to the therapeutic part of the study after validation by the Steering Committee.
  • Patients displaying abnormal/unexpected biodistribution of OTSA101-DTPA-111In, safety concerns and/or overt sign of disease progression will be taken off the study and other therapeutic plan will be envisaged.

PART 2: Therapeutic dose of OTSA101-DTPA-90Y OTSA101-DTPA-90Y will be administered IV as a single injection on Day 0 (i.e. 14 days after the injection of OTSA101-DTPA-111In - A 1week-delay [i.e. +7 days] is authorized from the planned D0).

Twelve (12) patients should be randomized in the PART 2 and treated with OTSA101-DTPA-90Y at two initial dose levels (6 patients per dose level):

  • Arm A: 1.5 mg of OTSA101-DTPA radiolabeled with 370MBq of 90Y (Dose level 1 (DL1)
  • Arm B: 1.5 mg of OTSA101-DTPA radiolabeled with 1110 MBq of 90Y (Dose level 2 (DL2)

Based on safety and preliminary efficacy data, a third dose level will be evaluated in 6 additional patients:

  • Arm C: 3 mg of OTSA101-DTPA radiolabeled with 2220 MBq of 90Y (Dose level 3 (DL3).

Such a study design will allow the determination of an optimal and recommended dose, surrounded by a lower suboptimal dose and a higher maximal tolerated (or possibly toxic) dose.

The first 3 patients will be enrolled at Centre Léon Bérard. Following the randomization of the first 2 patients, the accrual will be stopped for a maximal period of 1 month. The safety data will be reviewed every 2 randomized patients. Thee benefit/risk ratio will be regularly reviewed by the iDSMB and the Steering Committee (See Section Study Committee).

A compassionate program is planned for all randomized patients who derive clinical benefit from the study drug (at least stable disease and acceptable tolerance). A maximum of 4 injections per year will be planned. Subsequent injection will be performed provided that the eligibility criteria (except criteria related to previous treatment) are met before the day of administration. All inclusion in the compassionate program will be validated by the Steering Committee.

Being tested
OTSA101-DTPA-90Y level 1, OTSA101-DTPA-90Y level 2, OTSA101-DTPA-90Y level 3
Keywords
cancer, relapse or refractory
Medical subject headings
Sarcoma, Synovial, Neoplasms, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • OTSA101-DTPA-90Y level 1Drug

    Part 2 of the study 1.5 mg of OTSA101-DTPA radiolabelled with 370MBq of 90Y will be administered IV as a single injection on Day 0.

  • OTSA101-DTPA-90Y level 2Drug

    Part 2 of the study 1.5 mg of OTSA101-DTPA radiolabelled with 1110 MBq of 90Y will be administered IV as a single injection on Day 0.

  • OTSA101-DTPA-90Y level 3Drug

    Part 2 of the study 3 mg of OTSA101-DTPA radiolabelled with 2220 MBq of 90Y will be administered IV as a single injection on Day 0.

    This third dose level evaluation will be based on safety and preliminary efficacy data.

Study groups in NCT01469975
Study groupRoleWhat they receive
Arm A: Dose level 1Experimental1.5 mg of OTSA101-DTPA radiolabelled with 370MBq of 90Y
Receives: Drug: OTSA101-DTPA-90Y level 1
Arm B: Dose level 2Experimental1.5 mg of OTSA101-DTPA radiolabelled with 1110 MBq of 90Y
Receives: Drug: OTSA101-DTPA-90Y level 2
Arm C: Dose level 3Experimental3 mg of OTSA101-DTPA radiolabelled with 2220 MBq of 90Y
Receives: Drug: OTSA101-DTPA-90Y level 3

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Part 1: Biodistribution and binding of OTSA101-DTPA-111In

    Limiting Event is defined as unacceptable/unexpected biodistribution/binding of the mAb, and/or absence of tumor uptake. Data review will be performed on a patient per patient basis. The Biodistribution and binding of OTSA101-DTPA-111In will be analyzed. The rate of Limiting Event will be summarized by a proportion together with its 95% confidence interval.

    Measured: 144 hours post-dose (dose administered at day -14)

  2. Part 2: Safety profile

    The safety profile will be summarized with descriptive statistics including the following:

    • Occurrence of Severe Toxicities during the first 8 weeks post-injection of OTSA101-DTPA-90Y.
    • Occurrence of adverse events and serious adverse events during the study treatment period, including laboratory abnormalities, according to CTCAE v4.0 criteria.
    • Optimal recommended dose, defined as the dose level of OTSA101-DTPA-90Y with the best benefice-risk ratio taking into account the preliminary efficacy and safety data.

    Measured: During 1 year after randomization (day 0)

Secondary outcomes (6)

  1. Part 1: Pharmacokinetics parameters

    The following PK parameters will be collected: Cmax, tmax, t½: terminal half-life; AUC, Cl, Vss: Volume of distribution. These PK parameters will be calculated using non-compartmental analysis.

    Measured: They will be collected before the injection, (day -14) at 1, 2, 5, 24, 48, 72, 144 hours post dose and 7 days before randomisation

  2. Part 1: Safety profile of OTSA101-DTPA-111In

    The safety profile of OTSA101-DTPA-111In will be summarized with descriptive statistics. The occurrence of adverse events and serious adverse events during the whole imaging part, including laboratory abnormalities, will be summarized by a proportion together with its 95% confidence interval.

    Measured: During 14 days

  3. Part 2: Overall response rate

    The overall response rate is defined as the proportion of patients with a complete response or partial response on target lesions according to RECIST 1.1 criteria.

    Measured: At 6 and 12 weeks after treatment

  4. Part 2: Clinical benefit

    The clinical benefit rate is defined as the proportion of patients with a complete response or partial response or a stable disease on target lesions according to RECIST 1.1 criteria.

    Measured: At 6 and 12 weeks after treatment

  5. Part 2: Duration of response

    The duration of clinical response, measured from the time of first documented response until the first documented disease progression or death due to underlying cancer, will be described in responding subjects using descriptive statistics.

    Measured: At Week 6; Week12; Month 6; Month 9 and Month12 post Yttrium injection

  6. Part 2: Pharmacokinetics

    The following parameters will be collected: Cmax, tmax, t½: terminal half-life; AUC, Cl, Vss: Volume of distribution. Pharmacokinetics will be presented as descriptive statistics. Dose proportionality will be evaluated when applicable by an ANOVA mixed model. Accumulation will be assessed by Wilcoxon signed rank test.

    Measured: They will be collected before the injection, (day 0) at 1, 5, 24, 48 hours post dose and 14, 28 days post dose and at the end of the study

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Nov 2011 (estimated)
  2. Study startDec 2011
  3. Primary completion3 Feb 2015
  4. Study completion30 Jun 2015

Why it stopped: Too slow accrual.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01469975
Sponsor's protocol ID
SYNFRIZZ
Other IDs
2011-002574-23, ET11-062
Acronym
SYNFRIZZ
Status last verified
May 2017
First submitted
3 Nov 2011
Last updated
17 May 2017
Results posted
No
Data monitoring committee
Yes

Publications

  • Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300. doi: 10.3322/caac.20073. Epub 2010 Jul 7.

    PubMed 20610543

  • Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med. 2005 Aug 18;353(7):701-11. doi: 10.1056/NEJMra041866. No abstract available.

    PubMed 16107623

  • Ducimetiere F, Lurkin A, Ranchere-Vince D, Decouvelaere AV, Isaac S, Claret-Tournier C, Suignard Y, Salameire D, Cellier D, Alberti L, Bringuier PP, Blay JY, Ray-Coquard I. [Incidence rate, epidemiology of sarcoma and molecular biology. Preliminary results from EMS study in the Rhone-Alpes region]. Bull Cancer. 2010 Jun;97(6):629-41. doi: 10.1684/bdc.2010.1117. French.

    PubMed 20504759

  • Ladanyi M. Fusions of the SYT and SSX genes in synovial sarcoma. Oncogene. 2001 Sep 10;20(40):5755-62. doi: 10.1038/sj.onc.1204601.

    PubMed 11607825

  • Okcu MF, Munsell M, Treuner J, Mattke A, Pappo A, Cain A, Ferrari A, Casanova M, Ozkan A, Raney B. Synovial sarcoma of childhood and adolescence: a multicenter, multivariate analysis of outcome. J Clin Oncol. 2003 Apr 15;21(8):1602-11. doi: 10.1200/JCO.2003.07.008.

    PubMed 12697886

  • Trassard M, Le Doussal V, Hacene K, Terrier P, Ranchere D, Guillou L, Fiche M, Collin F, Vilain MO, Bertrand G, Jacquemier J, Sastre-Garau X, Bui NB, Bonichon F, Coindre JM. Prognostic factors in localized primary synovial sarcoma: a multicenter study of 128 adult patients. J Clin Oncol. 2001 Jan 15;19(2):525-34. doi: 10.1200/JCO.2001.19.2.525.

    PubMed 11208847

  • Laor T. MR imaging of soft tissue tumors and tumor-like lesions. Pediatr Radiol. 2004 Jan;34(1):24-37. doi: 10.1007/s00247-003-1086-3. Epub 2003 Dec 12.

    PubMed 14673551

  • Lewis JJ, Antonescu CR, Leung DH, Blumberg D, Healey JH, Woodruff JM, Brennan MF. Synovial sarcoma: a multivariate analysis of prognostic factors in 112 patients with primary localized tumors of the extremity. J Clin Oncol. 2000 May;18(10):2087-94. doi: 10.1200/JCO.2000.18.10.2087.

    PubMed 10811674

  • Singer S, Baldini EH, Demetri GD, Fletcher JA, Corson JM. Synovial sarcoma: prognostic significance of tumor size, margin of resection, and mitotic activity for survival. J Clin Oncol. 1996 Apr;14(4):1201-8. doi: 10.1200/JCO.1996.14.4.1201.

    PubMed 8648375

  • Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet. 1997 Dec 6;350(9092):1647-54.

    PubMed 9400508

  • Sleijfer S, Ouali M, van Glabbeke M, Krarup-Hansen A, Rodenhuis S, Le Cesne A, Hogendoorn PC, Verweij J, Blay JY. Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: an exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). Eur J Cancer. 2010 Jan;46(1):72-83. doi: 10.1016/j.ejca.2009.09.022.

    PubMed 19853437

  • Le Cesne A, Blay JY, Judson I, Van Oosterom A, Verweij J, Radford J, Lorigan P, Rodenhuis S, Ray-Coquard I, Bonvalot S, Collin F, Jimeno J, Di Paola E, Van Glabbeke M, Nielsen OS. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol. 2005 Jan 20;23(3):576-84. doi: 10.1200/JCO.2005.01.180.

    PubMed 15659504

  • Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schoffski P, Collin F, Pandite L, Marreaud S, De Brauwer A, van Glabbeke M, Verweij J, Blay JY. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol. 2009 Jul 1;27(19):3126-32. doi: 10.1200/JCO.2008.21.3223. Epub 2009 May 18.

    PubMed 19451427

  • Fletcher CD. The evolving classification of soft tissue tumours: an update based on the new WHO classification. Histopathology. 2006 Jan;48(1):3-12. doi: 10.1111/j.1365-2559.2005.02284.x.

    PubMed 16359532

  • Lee YF, John M, Edwards S, Clark J, Flohr P, Maillard K, Edema M, Baker L, Mangham DC, Grimer R, Wooster R, Thomas JM, Fisher C, Judson I, Cooper CS. Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. Br J Cancer. 2003 Feb 24;88(4):510-5. doi: 10.1038/sj.bjc.6600766.

    PubMed 12592363

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing OTSA101-DTPA-90Y level 1, OTSA101-DTPA-90Y level 2 and OTSA101-DTPA-90Y level 3 in people with Sarcoma, Synovial, run by Centre Leon Berard at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 17 May 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Too slow accrual.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Part 1: Biodistribution and binding of OTSA101-DTPA-111In (time frame: 144 hours post-dose (dose administered at day -14)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01469975, which also lists 50 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 May 2017.

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