Clinical trial NCT04143711: Study of DF1001 in Patients with Advanced Solid Tumors
Official title: A Phase I/II, First-In-Human, Multi-Part, Open-Label, Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of DF1001 in Patients with Locally Advanced or Metastatic Solid Tumors, and Expansion in Selected Indications
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Solid Tumor, Adult
Keywords: HER-2
NK Cell
Immunotherapy
Metastatic Breast Cancer
Non-small Cell Lung Cancer
Erbb2
DF1001
Sacituzumab Govitecan-hziy
Lead sponsor: Dragonfly Therapeutics
Sponsor class: INDUSTRY
First posted: 2019-10-29
Enrollment: 378
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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 .

Primary outcomes:
measure: Assessment of number of dose limiting toxicities experienced on study as defined per criteria in the study protocol
timeFrame: First 3 weeks of treatment for each subject.
measure: Assess Overall Response Rate
timeFrame: Through 90 days after completion of the study, an average of 1 year.
measure: Assess number of adverse events observed during treatment with DF1001 in combination with Nivolumab
timeFrame: Screening visit up to 28 days after last treatment on study.
measure: Assess number of adverse events observed during treatment with DF1001 in combination with Nab paclitaxel
timeFrame: Screening visit up to 28 days after last treatment on study.
measure: Assess number of adverse events observed during treatment with DF1001 in combination with Sacituzumab govitecan-hziy
timeFrame: Screening visit up to 28 days after last treatment on study.
Secondary outcomes:
measure: Evaluation of DF1001 Pharmacokinetics
timeFrame: From start of treatment up through 28 days after last treatment.
measure: Evaluation of DF1001 Immunogenicity
timeFrame: Every 3 weeks up to 28 days after last treatment.
measure: Assess Overall Survival (OS) Time.
timeFrame: Time from enrollment in the study until death, measured up to 2 years after last treatment on study.
measure: Assess Overall Response Rate by Investigator Assessment.
timeFrame: From time of initiation of therapy until the date of first documented tumor progression, assessed up to 24 months
measure: Assess Duration of Response by Investigator Assessment.
timeFrame: From time of initiation of therapy until the date of first documented tumor progression, assessed up to 24 months
measure: Assess Best Overall Response by Investigator Assessment.
timeFrame: Through 90 days after completion of the study, an average of 1 year.
measure: Assess Progression-free Survival by Investigator Assessment.
timeFrame: From time of initiation of therapy until the date of first documented tumor progression, assessed up to 24 months
Other outcomes:
Locations:
city: Irvine
country: United States
facility: University of California Irvine Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: San Diego
country: United States
facility: Sharp Healthcare
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Westwood
country: United States
facility: University of Kansas Medical Center Research Institute, Inc.
state: Kansas
city: New Orleans
country: United States
facility: Louisiana State University
state: Louisiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Bronx
country: United States
facility: Montefiore Einstein Center for Cancer Care
state: New York
city: New York
country: United States
facility: Icahn School of Medicine: Tisch Cancer Institute at Mount Sinai Medical Center
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Tacoma
country: United States
facility: Multicare Health System Tacoma General Hospital
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Arlon
country: Belgium
facility: Centre Hospitalier de l'Ardenne
city: Charleroi
country: Belgium
facility: Grand Hopital de Charleroi
city: Liège
country: Belgium
facility: Domaine Universitaire du Sart Tilman; CHU de Liege
city: Copenhagen
country: Denmark
facility: Rigshospitalet
state: Hovedstaden
city: Herlev
country: Denmark
facility: Herlev og Gentofte Hospital
city: Bordeaux
country: France
facility: Groupe Hospitalier Saint Andre
city: Dijon
country: France
facility: Centre Georges-Francois Leclerc
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Montpellier
country: France
facility: Institut Regional du Cancer de Montepelier
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Groupe Hospitalier Pitie Salpetriere
city: Rennes
country: France
facility: CHU de Rennes Hopital Pontechaillou
city: Saint Herblain
country: France
facility: ICO - Site Rene Gauducheau
city: Toulouse Cedex 09
country: France
facility: Institut Claudius Regaud
city: Busan
country: Korea, Republic of
facility: Inje University Haeundae Paik Hospital
city: Busan
country: Korea, Republic of
facility: Kosin University Gospel Hospital
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Ajou University Hospital
city: Gyeonggi-do
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Maastricht
country: Netherlands
facility: Maasticht University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
city: Utrecht
country: Netherlands
facility: UMC Utrecht
Study officials:
References: