This study has been transitioned to CTIS with ID 2023-503291-24-00 check the CTIS register for the current data. Main objective:Dose Escalation Part:• To assess the safety and tolerability of DF1001 monotherapy, and to determine the Maximum…
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Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
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.
Background summary
The development of checkpoint inhibitors (CPIs; ie, an anti-programmed cell
death protein 1 [anti-PD-1] or an anti-PD-ligand 1 protein [anti-PD-L1]
antibody) has transformed the treatment of many tumor types. However, even for
diseases where they are approved, CPI are active only in a subset of patients,
providing no clinical benefit to many of them.
One of the reasons for the CPI failure is the absence of infiltrating immune
cells inside the tumor (cold tumors). On the opposite, CPI are active in tumors
for which the presence of immune cells inside the tumor and at tumor center and
invasive margins can be demonstrated (hot tumors). Efforts have been made to
attract immune-infiltrating cells inside the tumor micro-environment in order
to make these *cold* tumors *hot*, but so far, with limited results.
Dragonfly Therapeutics is developing a study drug, DF1001, to boost the immune
system (the body*s natural defense system) to kill cancer cells. Non-clinical
data support that DF1001 can inhibit cancer cell growth or directly kill cancer
cells through different mechanisms, even if the level of HER2 expression is
insufficient for an approved human epidermal growth factor receptor 2 (HER2)
targeting agent to be active. This provides strong rationale for studying tumor
indications with low HER2 expression, currently a major unmet medical need in a
variety of tumors.
Study objective
This study has been transitioned to CTIS with ID 2023-503291-24-00 check the CTIS register for the current data.
Main objective:
Dose Escalation Part:
• To assess the safety and tolerability of DF1001 monotherapy, and to determine
the Maximum Tolerated Dose (MTD) of DF1001 inpatients
with advanced (unresectable, recurrent, or metastatic) solid tumors.
• To assess the safety and tolerability of DF1001 monotherapy, DF1001 with
nivolumab and DF1001 with nab-paclitaxelcombination 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 withsacituzumab 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.
Secondary objective:
• 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 confirmedbest 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 sacituzumabgovitecan-hziy
• To further evaluate the PK of DF1001 monotherapy and evaluate the PK of
DF1001 combination therapy with sacituzumabgovitecan-hziy
Efficacy Expansion Part:
• To assess DOR for confirmed responses, confirmed BOR, and PFS of DF1001
according to RECIST 1.1
Study design
This study is a Phase I/II, open-label, dose escalation study with a
consecutive parallel-group efficacy expansion study.
Intervention
Patients enrolled in the Dose Escalation Part and in the Efficacy Expansion
Cohorts Part with DF1001 monotherapy, will receive DF1001 intravenously (IV)
over a period of
a) up to two hours, but no less than 1 hour, in 4-week treatment cycles, for
DL1 to DL10
b) at least 3 hours and up to 4 hours on Days 1, 8, and 15 of C1 and up to 2
hours but no less than 1 hour for all subsequent infusions in 4-week treatment
cycles, for DL11
For DL12 and higher of DF1001 all patients will receive 5 mg/kg dose on C1D1.
Beginning with the second administration of DF1001 and continuing for the
remainder of the treatment with DF1001, patients will receive the dose
corresponding to the cohort/DL in which they were enrolled. The dose of DF1001
will be calculated based on the weight of the patient determined on the first
day of each cycle.
Nivolumab, when indicated, will be administered at a dose of 480 mg via an IV
over a 30 minute infusion on Day 1 of each cycle, once every 4 weeks according
to its package insert.
Nab-paclitaxel will be used at a dose of 100 mg/m2 and administered IV over a
30 minute infusion at Day 1, Day 8, and Day 15 of a 28-day cycle according to
its package insert.
Study burden and risks
In a study like this one, every risk or side effect cannot be predicted. Each
person*s reaction to a study drug may be different. The participant may have a
side effect or be at risk for symptoms, illnesses, and/or complications that
could not be predicted by the study doctor or the Sponsor of this study. If
such side effects occur or get worse, the participant must inform the study
doctor immediately.
In this study, the study drug will be tested for the first time in humans. Some
patients who have received DF1001 as part of this study have experienced
reactions to the study drug during or immediately following the infusion. These
are called Infusion Related Reactions and can include symptoms such as nausea,
vomiting, fever, chills, rigors (shaking), or lowered blood pressure. The
studies performed in animals have not produced any result that indicate that
the drug will not be tolerated in humans. However, other investigational drugs
that are similar to the study drug have been tested in previous clinical
studies. The most frequent, notable side effects seen were: decrease in the
heart capacity to pump the blood; allergic reactions to the drug (rash, hives,
itching, trouble breathing, closing of the throat, swelling of the lips, tongue
or face), Rarely, death can occur. Other frequent side effects include: massive
tumor destruction that may need medical intervention; exaggerated immediate
reaction from the immune system right after the administration of the drug. The
study drug may cause the immune system to attack normal organs and cause side
effects in many parts of the body. These problems may include but are not
limited to lung problems (pneumonitis); intestinal problems (colitis) that can
rarely lead to tears or holes in the intestine; liver problems (hepatitis)
which can cause liver failure; hormone gland problems (especially the thyroid,
pituitary and adrenal glands, and pancreas).
The potential benefits to the participant may include improvement of his/her
condition or temporary relief of symptoms. The benefits are by no means
assured, as this is an investigational drug and the safety and effectiveness of
the study drug is still being studied.
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Inclusion criteria
General Inclusion criteria for all study parts:
- 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.
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.
Monotherapy Dose Escalation
Histologically or cytologically proven locally advanced or metastatic solid
tumors, for which no standard therapy exists, or standard therapy has
failed. HER2 expression by immunohistochemistry and/or erbb2
amplification and/or erbb2 activating mutations must be documented on
either archival tissue or fresh tumor biopsy.
Nivolumab Dose Escalation
Patients must be eligible to receive nivolumab per its label for a
malignancy of epithelial origin.
OR
Patients for which no standard therapy exists or standard therapy has
failed.
Nab paclitaxel Dose Escalation
Be eligible for treatment with nab-paclitaxel per its label, which includes
metastatic breast cancer, after failure of combination chemotherapy for
metastatic disease or relapse within 6 months of adjuvant
chemotherapy. In this case, additional inclusion criteria also includes no
exposure to taxanes in the last 6 months.
OR
Have a tumor that has no standard therapy or for which standard
therapy has failed. In this case, patients should also not have been
treated with a taxane over the last 6 months.
OR
First line advanced (unresectable/recurrent/metastatic) TNBC.
Phase 2 Efficacy Expansion Cohorts Patients must have one of the
following tumor types: Non-small cell lung cancer (NSCLC, HER2 low or erbb2
amplified),
Urothelial bladder cancer (UBC), Breast Cancer (HER2 high or HER2 low),
Gastric cancer (HER2 high or HER2 low), Adenocarcinoma of the esophagus (HER2
high or HER2 low)
or a solid tumor with overexpressing of rb-B2 Receptor Tyrosine Kinase 2 (erbb2
amplified).
Patients must meet all inclusion criteria specific to their tumor type, as
outlined in section 5.2.
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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-503291-24-00 |
| EudraCT | EUCTR2019-004706-10-NL |
| ClinicalTrials.gov | NCT04143711 |
| CCMO | NL74381.056.20 |