Soft Tissue Sarcoma
Conditions
Brief summary
Open label, randomized, controlled phase II study preceded by a safety run-in part in subjects with advanced or metastatic soft-tissue sarcoma.
Detailed description
Open label, randomized, controlled phase II study preceded by a safety run-in part in subjects with advanced or metastatic soft-tissue sarcoma. * Safety Run-in Part: Six (6) patients will be treated with 1000 mg/m2 dacarbazine (DTIC) on Day 1 every 3 weeks plus 13 µg/kg L19TNF on Days 1, 3 and 5 every 3 weeks to test for safety of the combination. Should unacceptable toxicities occur in ≥ 2 patients during an observation period from Day 1 to Day 21 (first cycle), enrollment will be stopped at this dose level and 6 patients will be treated sequentially with DTIC at 850 mg/m2 on Day 1 every 3 weeks plus 13 µg/kg L19TNF on Days 1, 3 and 5 every 3 weeks. * Tumor Activity Evaluation Part Approximately 86 patients will be enrolled and parallel assigned in a 1:1 fashion to one of two different arms, as follows: * Arm 1: Patients will receive DTIC on Day 1 every 3 weeks plus L19TNF on Days 1, 3 and 5 every 3 weeks. * Arm 2: Patients will receive DTIC on Day 1 every 3 weeks. During the conduct of the study, detailed safety parameters will be routinely reviewed by the DSMB.
Interventions
DRUGDacarbazine
Dacarbazine (DTIC), 1000 mg/m2 or 850 mg/m2 on Day 1 of every 21-day cycle (based on results and DSMB evaluation in the safety run-in part of the study)
DRUGonfekafusp alfa
L19TNF, 13 μg/kg, on Day 1, 3, and 5 of every 21-day cycle for a maximum of 6 induction cycles. Patients experiencing apparent or real benefit with minimal or acceptable toxicity from the first 6 cycles of treatment, can receive, at investigator's discretion, maintenance treatment of 13 μg/kg, on Day 1 every 21-day
Sponsors
Philogen S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Safety Run in: Six (6) Patients will be treated with 1000 or 850 mg/m2 dacarbazine (DTIC) on Day 1 every three weeks plus 13 µg/kg L19TNF on Days 1, 3 and 5 every three weeks to test for safety of the combination as evaluated by an independent Data Safety Monitoring Board (DSMB). Tumor Activity Evaluation Part Arm 1: Patients will receive DTIC on Day 1 and L19TNF on Days 1, 3 and 5 every 3 weeks. Arm 2: Patients will receive DTIC on Day 1 every 3 weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, 18 to 80 years of age. 2. Histologically or cytologically confirmed advanced unresectable or metastatic soft tissue sarcoma (STS), Grade 2 - 3 according to the FNLCC grading system. Participants with bone sarcomas including Ewing sarcoma, Kaposi's sarcoma and gastrointestinal stromal tumors (GIST) will be excluded. 3. Subjects who received at least two prior systemic therapies (e.g., anthracyclines, taxanes, ifosfamide, gemcitabine, trabectedin, pazopanib, eribulin) for advanced or metastatic disease including at least one prior therapy based on anthracyclines as monotherapy or in combination. Neoadjuvant and adjuvant therapies can be considered as a prior line of treatment if the time to recurrence from completion of treatment was ≤ 12 months. Previous therapy with anthracyclines is not compulsory in situations of contraindications to this class of drugs. All previous therapies must have completed ≥ 3 weeks (21 days) prior to study treatment start. 4. Evidence of disease progression after prior line of therapy for advanced or metastatic disease. 5. Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria v.1.1. If only one lesion is present at screening this lesion should not have been irradiated during previous treatments. 6. Life expectancy of at least 3 months in the judgment of the investigator. 7. ECOG ≤ 2. 8. Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of HBsAg and anti-HBcAg-Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV: HCV-RNA or HCV antibody test. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no current infection are eligible. 9. Female patients: negative serum pregnancy test at screening for women of childbearing potential (WOCBP)\*. WOCBP must agree to use, from the screening to six months following the last study administration of L19TNF and/or DTIC, highly effective contraception methods, as defined by the Recommendations for contraception and pregnancy testing in clinical trials issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Male patients: Male subjects able to father children must agree to use two acceptable methods of contraception throughout the study from the screening to six months following the last administration of L19TNF and/or DTIC (e.g. condom with spermicidal gel). Double-barrier contraception is required. 10. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. 11. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures. * Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
Exclusion criteria
1. Anti-cancer treatment with radiation therapy (with the exception of radiation of single lesions for palliative reasons, e.g. pain management which then are not taken as indicator lesions for iRECIST response), chemotherapy, targeted therapies, immunotherapy, hormones or other antitumor therapies within 3 weeks prior to study treatment start. 2. Subjects who participated in an investigational drug or device study within 3 weeks prior to study treatment start. 3. Previous treatment with TNF or L19TNF or DTIC. 4. Known history of allergy to intravenously administered human proteins/peptides/antibodies and any other constituent of the product. 5. Absolute neutrophil count (ANC) \< 1.5 x 109/L, platelets \< 100 x 109/L and hemoglobin (Hb) \< 9.0 g/dl, with the exception of values lower than these due to cytologically or histologically proven marrow metastasis, which will not constitute
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | The PFS rate will be assessed at 3 months. | Progression-free survival (PFS) in according to RECIST v.1.1. The duration is defined beginning from randomization to progression or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) | The ORR rate will be assessed at 3, 6, 9, 12 months. | Objective response rate (ORR, consisting of CR plus PR; only the non-irradiated lesions are measured) according to RECIST v.1.1 between arms. |
| Objective Response Rate (ORR) | The ORR rate will be assessed at 3, 6, 9, 12 months. | Objective Response Rate (ORR, consisting of iCR plus iPR; only the non-irradiated lesions are measured) according to iRECIST in Arm1. |
| Overall Survival (OS) | The OS will be calculated at 12, 18, 24 and 36 months. | Overall Survival (OS) will be assessed for all randomized patients. The duration is defined beginning from randomization to death from any cause. |
| HAFA assessment | At day 1 of week 1 and week 2; at day 1 from week 4 up to week 18; at week 22 (EoT) | Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19TNF. |
| Quality of life (HRQol) | EORTC Quality of Life Questionnaire C30 will be assessed baseline at 3, 6, 9 and 12 months and EOT visit (if not done already within 4 weeks prior) | Quality of life of L19TNF in combination with DTIC compared to DTIC alone as Health-related Quality of life (HRQol) |
| Adverse Events | Time Frame: From week 1 up to week 52 | Number of patients with adverse events (AEs) assessed on CTCAE v.4.03 |
Countries
France, Germany, Italy, Poland, Spain
Outcome results
None listed