Study of DF1001 in Patients With Advanced Solid Tumors

Solid Tumor, Adult Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04143711
• Other study ID #: DF1001-001
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 11, 2019
• Est. completion date: December 2026

Study information

• Verified date: January 2024
• Source: Dragonfly Therapeutics
• Contact: Sean Rossi
• Phone: 671-588-0086
• Email: Sean.Rossi[@]Dragonflytx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 378
• Est. completion date: December 2026
• Est. primary completion date: October 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 .

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumor, Adult

Intervention

Drug:
• DF1001
Immunotherapy agent targeting NK cells.
• Nivolumab
Anti-PD-1 immunotherapy agent
• Nab paclitaxel
A chemotherapy treatment combining paclitaxel with albumin
• Sacituzumab Govitecan-hziy
A Trop-2 (Tumor-associated calcium signal transducer 2) directed antibody and topoisomerase inhibitor drug conjugate

Locations

Country	Name	City	State
Belgium	Centre Hospitalier de l'Ardenne	Arlon
Belgium	Grand Hopital de Charleroi	Charleroi
Belgium	Domaine Universitaire du Sart Tilman; CHU de Liege	Liège
Denmark	Rigshospitalet	Copenhagen	Hovedstaden
Denmark	Herlev og Gentofte Hospital	Herlev
France	Groupe Hospitalier Saint Andre	Bordeaux
France	Centre Oscar Lambret	Lille
France	Centre Leon Berard	Lyon
France	Institut Paoli Calmettes	Marseille
France	Institut Curie	Paris
France	ICO - Site Rene Gauducheau	Saint Herblain
France	Institut Claudius Regaud	Toulouse Cedex 09
Netherlands	Amsterdam University Medical Center	Amsterdam
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Maasticht University Medical Center	Maastricht
Netherlands	Radboud University Nijmegen	Nijmegen
Netherlands	Erasmus University Medical Center	Rotterdam
Netherlands	UMC Utrecht	Utrecht
United States	University of Michigan	Ann Arbor	Michigan
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Montefiore Einstein Center for Cancer Care	Bronx	New York
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	The Ohio State University	Columbus	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of California Irvine Medical Center	Irvine	California
United States	University of Southern California	Los Angeles	California
United States	University of Wisconsin	Madison	Wisconsin
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Louisiana State University	New Orleans	Louisiana
United States	Icahn School of Medicine: Tisch Cancer Institute at Mount Sinai Medical Center	New York	New York
United States	University of Pennsylvania, Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Sharp Healthcare	San Diego	California
United States	University of California San Francisco	San Francisco	California
United States	Multicare Health System Tacoma General Hospital	Tacoma	Washington
United States	University of Kansas Medical Center Research Institute, Inc.	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Dragonfly Therapeutics

Countries where clinical trial is conducted

United States,  Belgium,  Denmark,  France,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assessment of number of dose limiting toxicities experienced on study as defined per criteria in the study protocol	To assess the number of adverse events experienced during the study that meet dose limiting toxicity criteria per the study protocol.	First 3 weeks of treatment for each subject.
Primary	Assess Overall Response Rate	To assess the confirmed Overall Response Rate (ORR) per RECIST version 1.1 criteria by Investigator Assessment in the Efficacy Phase.	Through 90 days after completion of the study, an average of 1 year.
Primary	Assess number of adverse events observed during treatment with DF1001 in combination with Nivolumab	To assess the safety of DF1001 in Combination therapy with nivolumab by measuring Number of subjects with Treatment-Emergent Adverse Events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0	Screening visit up to 28 days after last treatment on study.
Primary	Assess number of adverse events observed during treatment with DF1001 in combination with Nab paclitaxel	To assess the safety of DF1001 in Combination therapy with Nab paclitaxel by measuring Number of subjects with Treatment-Emergent Adverse Events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0	Screening visit up to 28 days after last treatment on study.
Primary	Assess number of adverse events observed during treatment with DF1001 in combination with Sacituzumab govitecan-hziy	To assess the safety of DF1001 in Combination therapy with Sacituzumab govitecan-hziy by measuring Number of subjects with Treatment-Emergent Adverse Events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0	Screening visit up to 28 days after last treatment on study.
Secondary	Evaluation of DF1001 Pharmacokinetics	Concentration vs time of DF1001 will be measured using blood samples taken a various time points on study	From start of treatment up through 28 days after last treatment.
Secondary	Evaluation of DF1001 Immunogenicity	Evaluate the immunogenicity of DF1001 by measuring the number of patients developing anti-DF1001 antibodies	Every 3 weeks up to 28 days after last treatment.
Secondary	Assess Overall Survival (OS) Time.	To assess Overall Survival (OS)	Time from enrollment in the study until death, measured up to 2 years after last treatment on study.
Secondary	Assess Overall Response Rate by Investigator Assessment.	To assess confirmed and unconfirmed Overall Response Rate (ORR) by Investigator Assessment for patients enrolled in the dose escalation phase.	From time of initiation of therapy until the date of first documented tumor progression, assessed up to 24 months
Secondary	Assess Duration of Response by Investigator Assessment.	To assess Duration of Response (DOR) for confirmed responses by Investigator Assessment for patients enrolled in the dose escalation phase and in the efficacy expansion phase.	From time of initiation of therapy until the date of first documented tumor progression, assessed up to 24 months
Secondary	Assess Best Overall Response by Investigator Assessment.	To assess confirmed Best Overall Response by Investigator Assessment for patients enrolled in the dose escalation phase and in the efficacy expansion phase.	Through 90 days after completion of the study, an average of 1 year.
Secondary	Assess Progression-free Survival by Investigator Assessment.	To assess Progression-free Survival (PFS) by Investigator Assessment for patients enrolled in the dose escalation phase and in the efficacy expansion phase.	From time of initiation of therapy until the date of first documented tumor progression, assessed up to 24 months