Clinical Drug Experience Knowledgebase

Criteria

Inclusion Criteria: General (applies to all cohorts)

Signed written informed consent.
Male or female patients aged ≥ 18 years.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study entry and an estimated life expectancy of at least 3 months.
Baseline Left Ventricular Ejection Fraction (LVEF) ≥ 55% measured by echocardiography (preferred) or multigated acquisition (MUGA) scan.
Adequate hematological function.
Adequate hepatic function.
Adequate renal function.
Effective contraception for women of child bearing potential (WOCBP) patients as defined by World Health Organization (WHO) guidelines for 1 "highly effective" method or 2 "effective" methods.

Inclusion Criteria: Dose Escalation

Evidence of objective disease, but participation does not require a measurable lesion.
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.

Inclusion Criteria: "3+3" Nivolumab Combination Cohort

Eligible to receive nivolumab per its label for a malignancy of epithelial origin; or
Have no standard therapy available, or standard therapy has failed, and must not have received nivolumab prior to joining the study.
HER2 expression by immunohistochemistry and/or erbb2 amplification and/or erbb2 activating mutations must be documented on either archival tissue or fresh tumor biopsy.

Inclusion Criteria: "3+3" Nab paclitaxel Combination Cohort

Patients must 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 include also no exposure to taxanes in the last 6 months, OR
Patients whose tumor 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
HER2 expression by immunohistochemistry and/or erbb2 amplification and/or erbb2 activating mutations must be documented on either archival tissue or fresh tumor biopsy

Inclusion Criteria: Safety/PK/PD Expansion Cohorts (Monotherapy and Combination Therapy)

Fresh tumor biopsy must be obtained during the screening window.
HER2 expression by immunohistochemistry (IHC).
Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.

Inclusion Criteria: Urothelial Bladder Cancer Expansion Cohort(s)

Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary urothelial, urethra).
Patients must have radiographic disease progression after their last line of therapy.
Patients must have received a platinum containing chemotherapy and an anti PD-1 or anti PD-L1 for the treatment of urothelial bladder cancer.
Patients must have experienced radiographic progression of disease during treatment with PD-1/PD-L1 containing therapy.
Patients must have at least 1+ expression of HER2 by IHC.
For patients that will receive DF1001 in combination with nivolumab: progression while under anti PD-(L)1 must have occurred within 6 months of patient inclusion
A fresh tumor biopsy must be obtained during the screening window.

Inclusion Criteria: Breast Cancer (HER2 Low) Expansion Cohort

Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1
Histologically documented (metastatic or locally advanced) breast cancer.
Absence of erbb2 amplification by ISH and/or HER2 IHC of 0, 1+, or 2+. If Herceptest score is 0, HER2 must be detected by IHC on at least 1+ of the tumor cells.
Patient must have progressed after one line of systemic chemotherapy. Treatment with a trastuzumab-containing ADC will be considered as a line of chemotherapy.
Patients must have progressed (radiographically) after their last line of systemic therapy.
HR-positive patients must have received hormone therapy and have progressed while receiving hormone therapy.
A fresh tumor biopsy must be obtained during the screening window.

Inclusion Criteria: Breast Cancer (HER2 High) Expansion Cohort

Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1
Histologically documented (metastatic or locally advanced) breast cancer.
Erbb2 amplification by ISH and/or HER2 IHC of 3+, or 2+. If Herceptest score is 2+, ISH results should demonstrate erbb2 amplification.
Patient must have received trastuzumab, pertuzumab, and a HER2-targeting ADC. Other anti HER2 lines of therapy are acceptable.
Patient must have progressed after one line of systemic chemotherapy.
HR-positive patients must have received hormone therapy and have progressed while receiving hormone therapy.
A fresh tumor biopsy must be obtained during the screening window.

Inclusion Criteria: Basket erbb2 amplified Expansion Cohort

Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
Patients with any solid tumor except breast cancer, gastric cancer, or esophageal cancer that have progressed after an HER2 targeting ADC, or patients with carcinoma of the salivary glands that have progressed after one line of systemic therapy
Documented history of erbb2 amplification.
Patients must have received at least one line of an approved or established therapy.
A fresh tumor biopsy must be obtained during the screening window.

Inclusion Criteria: Gastric Cancer (HER2 High) Expansion Cohort

Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
Advanced (unresectable/recurrent/metastatic) gastric cancer or cancer of the gastro-esophageal junction.
Tumor must have been declared HER2 positive.
Patients must have received a first line of therapy that included a platinum salt and a fluoropyridine in combination with trastuzumab or a biosimilar to trastuzumab.
Patients must have progressed after the first line therapy.
Patients must have received only one line of therapy for the treatment of metastatic disease.
A fresh tumor biopsy must be obtained during the screening window.

Inclusion Criteria: Gastric Cancer (HER2 Low) Expansion Cohort

Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
Advanced (unresectable/recurrent/metastatic) gastric cancer or cancer of the gastro-esophageal junction.
Tumor must have been declared HER2 low; ISH non-amplified and/or HER2 IHC of 0, 1+ or 2+. If Herceptest score is 0, HER2 must be detected by IHC on at least 1+ of the tumor cells.
Patients must have received a first line of therapy that included a platinum salt and a fluoropyridine in combination with an anti PD-1
Patients must have progressed after the first line therapy.
Progression while under anti PD-(L)1 must have occurred within 6 months of patient inclusion
Patients must have received only one line of therapy for the treatment of metastatic disease.
Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
A fresh tumor biopsy must be obtained during the screening window.

Inclusion Criteria: Esophageal Cancer (HER2 High) Expansion Cohort

Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
Advanced (unresectable/recurrent/metastatic) esophageal cancer.
Tumor must have been declared HER2 positive.
Patients must have received a first line of therapy that included a platinum salt and a fluoropyridine in combination with trastuzumab or a biosimilar to trastuzumab.
Patients must have progressed after the first line therapy.
Patients must have received only one line of therapy for the treatment of metastatic disease.
A fresh tumor biopsy must be obtained during the screening window.

Inclusion Criteria: Esophageal Cancer (HER2 Low) Expansion Cohort

Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
Advanced (unresectable/recurrent/metastatic) esophageal cancer.
Tumor must have been declared HER2 low; ISH non-amplified and/or HER2 IHC of 0, 1+ or 2+. If Herceptest score is 0, HER2 must be detected by IHC on at least 1+ of the tumor cells.
Patients must have received a first line of therapy that included a platinum salt and a fluoropyridine in combination with an anti PD-1
Patients must have progressed after the first line therapy.
Progression while under anti PD-(L)1 must have occurred within 6 months of patient inclusion
Patients must have received only one line of therapy for the treatment of metastatic disease.
Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
A fresh tumor biopsy must be obtained during the screening window.

Inclusion Criteria: Non-small Cell Lung Cancer (HER2 Low) Expansion Cohort

Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
Histologically confirmed NSCLC meeting stage criteria for stage IIIB, stage IV, or recurrent disease that has been confirmed to have HER2 expression (at least 1+, however, patients must not carry an erbb2 amplification) via archival or fresh biopsy tissue prior to study enrollment.
Patients must have recurrent or progressive disease during or after platinum doublet-based chemotherapy OR must have recurrent or progressive disease within 6 months after completing platinum-based chemotherapy for local disease, including those with actionable genetic alterations.
Patients must have received and progressed on or after anti-PD-(L)1 therapy including those with actionable genomic alterations for which an approved treatment exists
Progression while under anti PD-(L)1 must have occurred within 6 months of patient inclusion
Status for actionable mutations (EGFR, ALK, ROS1, RET, etc.) must be known (when testing is available as per country/region standard of care practices); patients with actionable mutations must have received and progressed on, have been intolerant to, or not be a candidate for standard tyrosine kinase inhibitors (TKIs) (as available per country/region standard of care practices).
A fresh tumor biopsy must be obtained during the screening window.

Inclusion Criteria: Non-small Cell Lung Cancer (HER2 High) Expansion Cohort

Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
Histologically confirmed NSCLC meeting stage criteria for stage IIIB, stage IV, or recurrent disease that has been confirmed to have amplification of erbb2 via archival or fresh biopsy tissue prior to study enrollment.
Patients must have recurrent or progressive disease during or after platinum doublet-based chemotherapy OR must have recurrent or progressive disease within 6 months after completing platinum-based chemotherapy for local disease, including those with actionable genetic alterations.
Patients must have received and progressed on or after anti-PD-(L)1 therapy including those with actionable genomic alterations for which an approved treatment exists
Status for actionable mutations (EGFR, ALK, ROS1, RET, etc.) must be known (when testing is available as per country/region standard of care practices); patients with actionable mutations must have received and progressed on, have been intolerant to, or not be a candidate for standard tyrosine kinase inhibitors (TKIs) (as available per country/region standard of care practices).
Patients with an erbb2 amplification must provide archival tissue. If archival tissue is not available, a fresh biopsy must be obtained during the screening window.

Exclusion Criteria:

1. Concurrent treatment with a non-permitted drug as in Non-Permitted Medicines and Therapies section. Previous treatment with drugs that specifically target the HER2 pathway (mAb or tyrosine kinase inhibitor [TKI]) is acceptable providing washout period (4 weeks for mAbs or protein therapeutics and 2 weeks for a TKI).

2. Concurrent anticancer treatment (eg, cytoreductive therapy, radiotherapy [with the exception of palliative bone directed radiotherapy], immune therapy, or cytokine therapy except for erythropoietin), major surgery (excluding prior diagnostic biopsy), concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any investigational drug within 28 days before the start of study treatment. Short-term administration of systemic steroids (i.e., for allergic reactions or the management of immune-related adverse events [irAEs]) is allowed.

Note: Patients receiving bisphosphonates are eligible provided treatment was initiated at least 14 days before the first dose of DF1001.
Previous malignant disease other than the target malignancy to be investigated in this study within the last 3 years, with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ.
Rapidly progressive disease.
Active or history of central nervous system (CNS) metastases.
Receipt of any organ transplantation including autologous or allogeneic stem-cell transplantation.
Significant acute or chronic infections (including historic positive test for human immunodeficiency virus [HIV], or active or latent hepatitis B or active hepatitis C tested during the screening window).
Preexisting autoimmune disease (except for patients with vitiligo) needing treatment with systemic immunosuppressive agents for more than 28 days within the last 3 years or clinically relevant immunodeficiencies (eg, dys-gammaglobulinemia or congenital immunodeficiencies), or fever within 7 days of Day 1.
Known severe hypersensitivity reactions to mAbs (≥ Grade 3 NCI-CTCAE v5.0), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of partly controlled asthma).
Persisting toxicity related to prior therapy > Grade 1 NCI-CTCAE v5.0, however alopecia and sensory neuropathy ≤ Grade 2 is acceptable.
Pregnancy or lactation in females during the study.
Known alcohol or drug abuse.
Serious cardiac illness
NYHA III of IV heart failure or systolic dysfunction (LVEF < 55%)
High-risk uncontrolled arrhythmias ie, tachycardia with a heart rate > 100/min at rest
Significant ventricular arrhythmia (ventricular tachycardia) or higher-grade Atrioventricular block (AV-block; second-degree AV-block Type 2 [Mobitz 2] or third-degree AV-block)
Angina pectoris requiring anti-anginal medication
Clinically significant valvular heart disease
Evidence of transmural infarction on ECG
Poorly controlled hypertension (defined by: systolic > 180 mm Hg or diastolic > 100 mm Hg)
Clinically relevant uncontrolled cardiac risk factors, clinically relevant pulmonary disease or any clinically relevant medical condition in the opinion of the Investigator that may limit participation in this study.
Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
All other significant diseases (e.g., inflammatory bowel disease), which, in the opinion of the Investigator, might impair the patient's ability to participate
Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
Legal incapacity or limited legal capacity.
Incapable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol .