| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic Solid Tumors, and Expansion in Selected Indications |
|
| E.1.1.1 | Medical condition in easily understood language |
| Locally Advanced or Metastatic Solid Tumors |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10027476 |
| E.1.2 | Term | Metastases |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Dose Escalation Part:
• To assess the safety and tolerability of DF1001 monotherapy, and to
determine the Maximum Tolerated Dose (MTD) of DF1001 in patients
with advanced (unresectable, recurrent, or metastatic) solid tumors.
• To assess the safety and tolerability of DF1001 monotherapy, DF1001
with nivolumab and DF1001 with nab-paclitaxel combination therapies
Exploratory Efficacy Part
• To assess key safety and tolerability of DF1001 monotherapy and
DF1001 combination therapy with sacituzumab govitecan-hziy.
• To evaluate the confirmed objective response rate (ORR) of DF1001
monotherapy and DF1001 combination therapy with sacituzumab
govitecanhziy.
Efficacy Expansion Cohorts Part:
• To assess the confirmed ORR according to the Response Evaluation
Criteria in Solid Tumors version 1.1 (RECIST 1.1) per Investigator
assessment. |
|
| E.2.2 | Secondary objectives of the trial |
Dose Escalation Part:
• To characterize the pharmacokinetics (PK), of DF1001 monotherapy
• To evaluate immunogenicity of DF1001, and to correlate to its
exposure and clinical activity
• To assess overall survival (OS)
• To assess unconfirmed and confirmed ORR, duration of response
(DOR) for confirmed responses, unconfirmed and confirmed best overall
response (BOR), and progression-free survival (PFS) according to
RECIST 1.1
Exploratory Efficacy Part:
• To evaluate DOR, disease control rate (DCR), progression-free survival
(PFS)
• To evaluate the OS
• To further assess the safety and tolerability of DF1001 monotherapy
and DF1001 combination therapy with sacituzumab govitecan-hziy
• To further evaluate the PK of DF1001 monotherapy and evaluate the
PK of DF1001 combination therapy with sacituzumab
govitecan-hziy
Efficacy Expansion Part:
• To assess DOR for confirmed responses, confirmed BOR, and PFS of
DF1001 according to RECIST 1.1 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Common Inclusion Criteria For All Groups/Cohorts/Combinations:
- Signed written informed consent.
- Male or female patients aged ≥ 18 years.
- ECOG performance status of 0 to 1 at study entry.
- Disease must be measurable with at least 1 unidimensional measurable
lesion by RECIST 1.1. (Not applicable to "Accelerated Titration and 3+3
Dose Escalation" cohorts.
- Baseline LVEF ≥ 55% measured by echocardiography (preferred) or
MUGA scan.
- Adequate hematological function defined by white blood cell (WBC)
count ≥ 3 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L,
lymphocyte count ≥ 0.5 × 109/L, platelet count ≥ 75 × 109/L (in Dose
Escalation, Safety/PK/PD, and Dose Expansion parts), platelet count ≥
100 × 109/L (in Efficacy Expansion part), and hemoglobin ≥ 9 g/dL
(may have been transfused but must show hematologic count stability
for 14 days from the time of transfusion to C1D1).
- Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the
upper limit of normal (ULN). Aspartate aminotransferase (AST) level ≤
2.5 × ULN, and an alanine aminotransferase (ALT) level ≤ 2.5 × ULN or,
for patients with documented metastatic disease to the liver, AST and
ALT levels ≤ 5 × ULN. Patients with known Gilbert Disease who have
serum bilirubin level ≤ 3 ULN may be enrolled.
- Adequate renal function defined by an estimated creatinine clearance ≥
50 mL/min according to the Cockcroft-Gault formula or another
calculation of measurement method as according to local standards.
- Subjects must be willing to use appropriate contraception as defined in
the protocol.
- Effective contraception for women of childbearing potential (WOCBP)
and male patients as defined by World Health Organization (WHO)
guidelines for 1 "highly effective" method or 2 "effective" methods.
CTFG. WOCBP require use of a highly effective contraceptive measure.
Contraception methods with low user dependency should preferably be
used, in particular when contraception is introduced as a result of
participation in the clinical trial for 120 days after last dose.
A male subject should use condom during treatment and until the end of
relevant systemic exposure in the male subject plus a further 90-day
period. For a non-pregnant WOCBP partner, contraception
recommendations should also be considered. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria for All Patients of Both Study Parts:
1. Previous treatment with drugs that specifically target the HER2 pathway (mAb or Tyrosine Kinase Inhibitor [TKI]) is acceptable providing washout period
2. Concurrent anticancer treatment, immune therapy, or cytokine therapy
3. Life expectancy of less than 3 months.
4. Active or history of central nervous system (CNS) metastases.
5. Receipt of any organ transplantation including autologous or allogeneic stem-cell transplantation.
6. Significant acute or chronic infections
7. Preexisting autoimmune disease needing treatment with systemic immunosuppressive agents ≥ 28 days within the last 3 years or clinically relevant immunodeficiencies (e.g, dys-gammaglobulinemia or congenital immunodeficiencies), or fever Grade 2 or higher within 7 days of Day 1.Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
8. Pregnancy or lactation in females during the study.
9. Serious cardiac illness or clinically relevant uncontrolled cardiac risk factors |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose escalation part:
• Occurrence of DLTs during the first 21 days of treatment.
• Number, severity, and duration of treatmentemergent adverse events
(TEAEs), treatmentrelated adverse events (trAEs), and serious adverse
events (SAEs) per Common Terminology Criteria for Adverse Events
(CTCAE) v5.0 (cytokine release syndromes will be reported using
American Society for Transplantation and Cellular Therapy [ASTCT]
criteria).
• Adverse events of special interest (AESI) and adverse events (AEs)
leading to treatment discontinuation.
Exploratory Efficacy Part:
• Number, severity, and duration of drug-related TEAEs for all cohorts
and those leading to treatment discontinuation, according to NCI-CTCAE
v5.
• The ORR, according to RECIST 1.1, per Investigator assessment.
Efficacy Expansion Part :
•The confirmed ORR, according to RECIST 1.1, per Investigator
assessment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
•Assessment of number of dose limiting toxicities experienced on study
as defined per criteria in the study protocol [ Time Frame: First 3 weeks
of treatment for each subject. ]
•Assess Overall Response Rate [ Time Frame: Through 90 days after
completion of the study, an average of 1 year. ] |
|
| E.5.2 | Secondary end point(s) |
Dose Escalation Part :
• PK profile.
• OS from initial treatment to death from any cause.
• Unconfirmed and confirmed ORR, DOR, unconfirmed and confirmed
BOR, and PFS according to RECIST 1.1, per Investigator
Assessment.
• Immunogenicity parameters.
Exploratory Efficacy Part :
• DOR for confirmed responses according to RECIST 1.1, per Investigator
assessment.
• DCR according to RECIST 1.1, per Investigator assessment.
• PFS according to RECIST 1.1, per Investigator assessment
• OS from initial treatment to death from any cause.
• SAEs.
• Number, severity, relationship, and duration of TEAEs for all cohorts,
according to the NCICTCAE v5.0.
• Number, severity, and duration of trAEs according to NCI-CTCAE v5.0.
• Physical examination.
• Vital sign measurements.
• clinical laboratory parameters.
• ECG parameters, Echocardiogram (ECHO) or multigated acquisition
(MUGA) scan findings.
• Anti-drug antibody.
• PK profile.
Efficacy Expansion Part
• DOR, confirmed BOR, and PFS per Investigator assessment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Serum concentrations of DF1001 determined at various time points from start up through 28 days after last treatment
•Evaluation of DF1001 immunogenicity every 3 weeks up to 28 days after last treatment
•Assess BOR through 90 days after completion of the study an average of 1 year
•Assess DOR from time of initiation of therapy until the date of first documented tumor progression assessed up to 2 years
•Assess PFS from time of initiation of therapy until the date of first documented tumor progression assessed up to 2 years
•Assess OS time from enrollment in the study until death measured up to 2 years after last treatment on study
•Assess number of AE observed during treatment with DF1001 in combination with Pembrolizumab screening visit up to 28 days after last treatment on study |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Parallel cohorts and one with pembrolizumab only for initial safety and possible signal finding |
|
| 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.8.2.4 | Number of treatment arms in the trial | 14 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| United States |
| Belgium |
| Denmark |
| France |
| Netherlands |
|
| 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
|
The end of the trial will be defined as 1 year after the last patient completes his/her EOT visit.
If the trial is not terminated for a reason given in Section 5.5 of the protocol (Early Termination of the Trial), the end of the trial is defined as 1 year after the last patient has received the last dose of DF1001. |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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