Study of DF1001 in Patients with Advanced Solid Tumors

DF1001-001 is a study of a new molecule that targets natural killer (NK) cells and T-cell activation signals to specific receptors on cancer cells. The study will occur in two phases. The first phase will be a dose escalation phase, enrolling patients with various types of solid tumors that express human epidermal growth factor receptor 2 (HER2). The second phase will include a dose expansion using the best dose selected from the first phase of the study. Multiple cohorts will be opened with eligible patients having either HER2 activated non-small cell lung cancer, hormone receptor (HR) positive HER2 negative metastatic breast cancer, or HER2 positive metastatic breast cancer. DF1001-001 will be administered as monotherapy or in combination; combinations are DF1001 + nivolumab, DF1001 + Nab paclitaxel, and DF1001 + sacituzumab govitecan-hziy.


Eligibility Criteria:
Inclusion Criteria: General (applies to all cohorts)

1. Signed written informed consent.
2. Male or female patients aged ≥ 18 years.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study entry and an estimated life expectancy of at least 3 months.
4. Baseline Left Ventricular Ejection Fraction (LVEF) ≥ 55% measured by echocardiography (preferred) or multigated acquisition (MUGA) scan.
5. Adequate hematological function.
6. Adequate hepatic function.
7. Adequate renal function.
8. 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: NSCLC (HER2 Activated) Exploratory Efficacy Cohorts - Monotherapy and Combination with Sacituzumab Govitecan-hziy.

1. Have progression of unresectable locally advanced or metastatic NSCLC after last systemic therapy (as confirmed by investigator) or be intolerant of last systemic therapy.
2. Have HER2 overexpression status (IHC 2+ or 3+), or ERBB2 amplification, or HER2 activating mutation
3. Have recurrent or progressive disease during or after platinum doublet-based chemotherapy.
4. Have received and progressed on or after anti-PD-(L)1 therapy.

Inclusion Criteria: Metastatic Breast Cancer (HR+/HER2-) Exploratory Efficacy Cohort - Monotherapy and Combination with Sacituzumab Govitecan-hziy.

1. Documented evidence of HR+ metastatic breast cancer
2. Documented evidence of HER2- status.
3. Disease progression or recurrence after prior therapy.

Inclusion Criteria: Metastatic Breast Cancer (HER2+) Exploratory Efficacy Cohorts - Combination with Sacituzumab Govitecan-hziy

1. Have histologically confirmed HER2+ breast cancer.
2. Have received prior treatment with trastuzumab, pertuzumab, ado-trastuzumab emtansine (T-DM1), or trastuzumab deruxtecan (T-DXd).
3. Have progression of unresectable locally advanced metastatic breast cancer after last systemic therapy or be intolerant of last systemic therapy.

Inclusion Criteria: Dose Escalation

1. Evidence of objective disease, but participation does not require a measurable lesion.
2. Locally advanced or metastatic solid tumors, for which no standard therapy exists, or standard therapy has failed.
3. HER2 expression by immunohistochemistry and/or erbb2 amplification and/or erbb2 activating mutations.

Inclusion Criteria: "3+3" Nivolumab Combination Cohort

1. Eligible to receive nivolumab per its label for a malignancy of epithelial origin; or
2. Have no standard therapy available, or standard therapy has failed, and must not have received nivolumab prior to joining the study.
3. HER2 expression by immunohistochemistry and/or ebb2 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

1. Patients must be eligible for treatment with nab-paclitaxel per its label, or have no standard therapy available, or standard therapy has failed.
2. 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).

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

Inclusion Criteria: Urothelial Bladder Cancer Expansion Cohort(s).

1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
2. Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary urothelial, urethra).
3. Patients must have received a platinum containing chemotherapy and an anti PD-1 or anti PD-L1 for the treatment of urothelial bladder cancer.

Inclusion Criteria: Breast Cancer (HER2 Low) Expansion Cohort

1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1
2. Histologically documented (metastatic or locally advanced) breast cancer.
3. Absence of erbb2 amplification by ISH and/or HER2 IHC of 0, 1+, or 2+.
4. Patient must have progressed after one line of systemic chemotherapy.

Inclusion Criteria: Breast Cancer (HER2 High) Expansion Cohort

1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1
2. Histologically documented (metastatic or locally advanced) breast cancer.
3. Erbb2 amplification by ISH and/or HER2 IHC of 3+, or 2+. If Herceptest score is 2+, ISH results should demonstrate erbb2 amplification.

Inclusion Criteria: Basket erbb2 amplified Expansion Cohort

1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
2. Documented history of erbb2 amplification.
3. Patients must have received at least one line of an approved or established therapy.

Inclusion Criteria: Gastric Cancer (HER2 High) Expansion Cohort

1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
2. Advanced (unresectable/recurrent/metastatic) gastric cancer or cancer of the gastro-esophageal junction.
3. Tumor must have been declared HER2 positive.

Inclusion Criteria: Gastric Cancer (HER2 Low) Expansion Cohort

1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
2. Advanced (unresectable/recurrent/metastatic) gastric cancer or cancer of the gastro-esophageal junction.
3. 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.

Inclusion Criteria: Esophageal Cancer (HER2 High) Expansion Cohort

1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
2. Advanced (unresectable/recurrent/metastatic) esophageal cancer.
3. Tumor must have been declared HER2 positive.

Inclusion Criteria: Esophageal Cancer (HER2 Low) Expansion Cohort

1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
2. Advanced (unresectable/recurrent/metastatic) esophageal cancer.
3. 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.

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

1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
2. 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.
3. Patients must have recurrent or progressive disease during or after platinum doublet-based chemotherapy.

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

1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1.
2. 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.
3. Patients must have recurrent or progressive disease during or after platinum doublet-based chemotherapy.

Exclusion Criteria:

1. 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 or 5 half-lives before the start of study treatment. Note: Patients receiving bisphosphonates are eligible provided treatment was initiated at least 14 days before the first dose of DF1001.
2. 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.
3. Rapidly progressive disease.
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 (including historic positive test for human immunodeficiency virus \[HIV\], or active or latent hepatitis B or active hepatitis C tested during the screening window).
7. 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.
8. 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).
9. Persisting toxicity related to prior therapy \> Grade 1 NCI-CTCAE v5.0, however alopecia and sensory neuropathy ≤ Grade 2 is acceptable.
10. Pregnancy or lactation in females during the study.
11. Known alcohol or drug abuse.
12. Serious cardiac illness
13. NYHA III of IV heart failure or systolic dysfunction (LVEF \< 55%)
14. High-risk uncontrolled arrhythmias ie, tachycardia with a heart rate \> 100/min at rest
15. 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)
16. Angina pectoris requiring anti-anginal medication
17. Clinically significant valvular heart disease
18. Evidence of transmural infarction on ECG
19. Poorly controlled hypertension (defined by: systolic \> 180 mm Hg or diastolic \> 100 mm Hg)
20. 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.
21. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
22. All other significant diseases (e.g., inflammatory bowel disease), which, in the opinion of the Investigator, might impair the patient's ability to participate
23. Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
24. Legal incapacity or limited legal capacity.
25. 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 .