| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066476 |
| E.1.2 | Term | Haematological malignancy |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
•to evaluate the safety and tolerability of Ti-061 in adult patients with advanced malignancies
•to evaluate the safety and tolerability of Ti-061 combined with pembrolizumab in adult patients with advanced malignancies. |
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| E.2.2 | Secondary objectives of the trial |
Part A:
•to recommend a dose and regimen of Ti-061 for further development.
•to determine the PK of Ti-061 in plasma.
•to determine the effect of Ti-061 on circulating markers of immunogenicity.
•to provide a preliminary estimate of efficacy of Ti-061 in patients with selected malignancies enrolled in expansion cohorts.
Part B:
•to recommend a dose and regimen of Ti-061 for further development in combination with pembrolizumab.
•to determine the PK of Ti-061 in combination with pembrolizumab in plasma.
•to determine the effect of Ti-061 on circulating markers of immunogenicity.
•to provide a preliminary estimate of efficacy of Ti-061 in combination with pembrolizumab in patients with selected tumors in expansion cohorts.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients meeting all of the following inclusion criteria at screening/day-1 of first dosing will be eligible for participation in the study.
1. Informed consent signed by the patient.
2. Male or female patients ≥18 years of age.
3. Histological or cytological diagnosis as follows:
a. In the escalation phase of the study, patients must have a histological or cytological diagnosis of melanoma or any type of carcinoma or sarcoma, progressive metastatic disease, or progressive locally advanced disease not amenable to local therapy. Part A only: Patients with metastatic breast cancer may have bone-only disease.
b. In the tumor-type-specific expansion cohorts, patients must have a histological diagnosis of the relevant tumor type. Refer to protocol for specific tumor types for Part A and Part B.
4. Prior therapies:
Refer to the protocol for further details on inclusion criteria on prior therapies for Part A and Part B of the study.
5. Patient must have demonstrated PD after the most recent treatment regimen (or within 3 months prior to enrollment in the case of treatment-naïve patients).
6. At least one non-target lesion for escalation cohorts and at least one target lesion not impacted by study biopsy, or two lesions if one is impacted by biopsy, for the expansion cohorts per RECIST 1.1 (Part A only: except for patients with HRpos MBC, who may have bone-only disease).
7. If not menopausal or surgically sterile, patients must be willing to practice at least one of the following methods of birth control for at least a (partner’s) menstrual cycle before and for 3 months after study drug administration: (1) Total abstinence from sexual intercourse with a member of the opposite sex; (2) Sexual intercourse with vasectomized male/sterilized female partner; (3) Hormonal female contraceptive (oral, parenteral, or transdermal) for at least 3 consecutive months prior to investigational product administration (Part A only: when not clinically contraindicated as in breast, ovarian and endometrial cancers); (4) Other acceptable forms of birth control (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicide or cream); (5) Use of an intrauterine contraceptive device.
8. Resolution of prior-therapy-related adverse effects (Part A: including immune-related adverse effects, but excluding alopecia; Part B: excluding alopecia and immune-related adverse effects of CPIs – see Exclusion #10) to ≤ Grade 1 per CTCAE, and no treatment for these AEs for at least 4 weeks prior to the time of enrollment.
9. Part A: Minimum of 2 weeks since last dose of other hormone therapy or 3 weeks since last dose of other systemic cancer therapy or radiotherapy (>6 weeks in case of nitrosureas, antibody-drug conjugate or radio-immuno conjugate therapy). Part B: Minimum of 12 weeks from the first dose of CPI and >4 weeks from the last dose of CPI and >3 weeks from last dose of other systemic cancer therapy or radiotherapy (>6 weeks in case of nitrosureas, antibody-drug conjugate or radio-immuno conjugate therapy).
10. Part B: For expansion cohorts allowing prior CPIs: resolution of CPI-related AEs (including irAEs) back to Grade 0-1 and ≤10 mg/day prednisone or equivalent for irAEs for at least two weeks prior to first dose of study drug. No history of severe irAEs from CPI CTCAE Grade 4 requiring steroid treatment. No history of CTCAE Grade 3 irAEs from CPI requiring steroid treatment (>10 mg/day prednisone or equivalent dose) for >12 weeks.
11. Has negative virology/serology for HIV-1, HIV-2, hepatitis B (surface antigen), and hepatitis C RNA by PCR.
12. Part B only: For patients with HCC, Child-Pugh A liver function.
13. Patient must have adequate organ function as indicated by the laboratory values outlined in the protocol.
14. Patient has agreed to a newly obtained biopsy of tumor (that can be biopsied based on investigator's assessment) and to providing the acquired tissue for biomarker analysis. Tissue obtained for the biopsy must not be previously irradiated. No systemic antineoplastic therapy may be received by the patient between the time of the biopsy and the first administration of study drug. An archival specimen is mandatory for all patients. Fresh tumor biopsies are mandatory for patients enrolled in the expansion cohorts. Patients who could not provide a fresh tumor biopsy at the time of enrollment can only be enrolled after discussion with the Sponsor.
15. Patient is able and willing to comply with the protocol and the restrictions and assessments therein. |
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| E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria at Screening/day -1 of first dosing will not be enrolled in the study:
1. Patient previously had a severe hypersensitivity reaction to treatment with another mAb.
2. Part B only: For patients in the expansion cohorts, history of intolerance to any anti-PD-(L)1.
3. Patient has ECOG PS >1.
4. Part A only: Prior treatment with a CPI (anti-PD-1, PD-L1 or CTLA-4).
5. Prior RBC transfusion within 3 months of screening.
6. Prior organ or stem cell transplant.
7. History of autoimmune hemolytic anemia or autoimmune thrombocytopenia.
8. Patients with a history of any condition known to be associated with reduced RBC lifespan e.g. Thalassemia trait, G6PD deficiency.
9. Patients with extensive (25%) disease involvement of bone marrow.
10. Patients with extensive (25%) irradiation of the bone marrow.
11. Part B only: History of pneumonitis or interstitial lung disease.
12. Patients with symptomatic ascites or pleural effusion. A patient who is clinically stable for at least two weeks following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
13. Patient has known active CNS primary tumor or metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry, have no evidence of new or enlarging brain metastases and are off steroids for at least 15 days prior to first dose of study drug.
14. Patient has a known history of a hematologic malignancy, malignant primary brain tumor, or of another malignant primary solid tumor (other than that under study), unless the patient has undergone potentially curative therapy with no evidence of that disease for 3 years.
Note: The time requirement for no evidence of disease for 3 years does not apply to the tumor for which a patient is enrolled in the study. The time requirement also does not apply to patients who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.
15. Patient has active infection requiring therapy.
16.
Part A: Use of systemic corticosteroids within 15 days or other immunosuppressive drugs within 30 days prior to start of the study.
Part B: Use of systemic corticosteroids >10 mg/day prednisone or equivalent within 15 days or other immunosuppressive drugs within 30 days prior to start of the study.
17. Part B: For patients who will receive pembrolizumab:
a. Prior thoracic radiation with a dose > 30 Gy within 26 weeks.
b. Patients with a tumor at a critical anatomic location, like abutting the thecal sac or compressing a main-stem bronchus, such that an impending catastrophic event is possible, should have that tumor lesion radiated prior to treatment.
c. Patient has risk factors for bowel obstruction or bowel perforation (examples include but not limited to a history of acute diverticulitis, intra-abdominal abscess, abdominal carcinomatosis).
18. Patient has received an investigational product or been treated with an investigational device within 30 days prior to first drug administration.
19. History or clinical evidence of any surgical or medical condition which the investigator judges as likely to interfere with the results of the study or pose an additional risk in participating e.g., rapidly progressive or uncontrolled disease involving a major organ system—vascular, cardiac, pulmonary, gastrointestinal, gynecologic, hematologic, neurologic, neoplastic, renal, endocrine, autoimmune or an immunodeficiency, or clinically significant active psychiatric or abuse disorders.
20. Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
21. Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and tolerability of Ti-061 alone and in combination with pembrolizumab. The primary analysis of safety will be a comprehensive evaluation of AEs and/or toxicity, presented by dose, regimen and tumor type cohort and overall, based on:
• Recording of AEs by CTCAE V4
• Recording of IRRs
• Results of monitoring vital signs
• Occurrence of late or cumulative AEs
• Occurrence of autoimmune AEs
• Results of clinical chemistry, hematology/coagulation, and urine analysis tests
• ECG results
• Changes in physical examination
• Markers of inflammation and immunogenicity
• Need for concomitant medications
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety assessments will be performed at the intervals indicated in the Schedule of Assessments (see Appendix 1 and Appendix 2 of the protocol) and at any time deemed necessary by the investigator.
AEs and SAEs (including abnormal laboratory test results) will be collected from the time of signing the informed consent until 30 days after the last Ti-061 dose. Only AEs/abnormalities occurring after the first dose of Ti-061 will be considered treatment-emergent. |
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| E.5.2 | Secondary end point(s) |
•Efficacy will be evaluated RECIST 1.1, but if progressive disease is seen at first evaluation, immune-related response criteria per irRECIST may be used by the investigator to continue therapy in the presence of pseudoprogression or tumor flare with clinical stability, as appropriate and per the guidelines for immunotherapies of solid tumors. For patients with MBC, clinical benefit response will also be assessed. Tumor assessments will be performed to assess disease response per RECIST 1.1 (CT/MRI).
•The following PK parameters of Ti-061 will be evaluated in plasma after IV administration: the maximum serum concentration (Cmax), the area under the concentration time curve to the last measurable concentration (AUCt), and accumulation (R). Dose proportionality will be assessed and, if appropriate, additional parameters will be reported, e.g. clearance (CL), and volume of distribution (Vz).
•Select serum cytokines and flow cytometry designed to assess changes in T-cell and macrophage activation after Ti-061 administration will be
sampled in a subset of patients.
•ADAs – the presence and frequency of ADAs will be measured
•IHC in current formalin-fixed paraffin embedded (FFPE) biopsy or archival tissue will be used to assess at a minimum CD47 and PD-L1, and if possible calreticulin, CD3 and CD68, and potentially other lymphocyte markers. H-scores and/or percentage cell staining will be reported for tumor cells and for identifiable subgroups of immune cells.
•CD47 receptor occupancy will be measured in red blood cells in all patients pre-treatment and at multiple timepoints on treatment. Appendix 1 of the protocol describes the sampling schedule. Target engagement of Ti-061 with CD-47 will be assessed in fresh biopsies from patients at selected sites.
•AEs and SAEs (including abnormal laboratory test results) will be collected from the time of signing the informed consent until 30 days after the last Ti-061 dose. Only AEs/abnormalities occurring after the first dose of Ti-061 will be considered treatment-emergent. A DLT is defined as a confirmed AE per CTCAE (as detailed below) within the 21 days of starting treatment with a reasonable chance to be related to the study drug(s) based upon the determination of the investigator (and subsequently the DRC). Once the two-tiered dose method is implemented, the DLT period will be extended to 28 days. For consideration of the MTD, any chronic grade ≥2 toxicity thought to be related to study drug will also be taken into account.
The following are considered DLTs:
1.Grade 4 hematologic toxicity, except for decreased platelet count which should be Grade 4 and require platelet transfusion.
2.Grade 4 non-hematologic toxicity (not laboratory).
3.Grade 3 non-hematologic toxicity (not laboratory) lasting >3 days despite optimal supportive care.
4.Any Grade 3 non-hematologic laboratory value if:
•Medical intervention is required to treat the patient, or
•The abnormality leads to hospitalization, or
•The abnormality persists for >1 week.
5.Febrile neutropenia Grade 3 or Grade 4:
•Grade 3 is defined as absolute neutrophil count (ANC) <1000/mm3
with a single temperature of >38.3 °C (101 °F) or a sustained temperature of ≥38 °C (100.4 °F) for more than one hour
•Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained temperature of ≥38 °C (100.4 °F) for more than one hour, with life-threatening consequences and urgent intervention indicated.
6.Grade 5 toxicity (i.e., death). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Efficacy will be evaluated every 9 weeks per RECIST 1.1 or irRECIST as appropriate. Plasma PK pre- and post-dose, & 2, 4, 8 & 12 hours after the start of the first infusion on D1, 24 hrs post-D1 infusion, 48 hours post-D1 infusion & 72hrs post-D1 infusion; pre- & postdose on D8 & D15 of C1 1, D1 and D8 of C2 and D1 and D8 of every cycle for first 6 mths; and D7, 14, & 30 after last dose. Cytokine/chemokine markers and complement fractions: 2 hrs post-dose at C1 D1, D8 and D15 in all patients, and D1 & D8 of each cycle in patients experiencing IRRs. ADAs: pre-dose D1 of each 3-week cycle. Paired biopsies at D21 on study will be requested from patients with accessible lesions for IHC. CD47 receptor occupancy will be measured pre-treatment and at multiple timepoints on treatment. |
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| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 8 |
| 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 |
| France |
| Netherlands |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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