Brief Title
Phase I-II, FIH, TROP2 ADC, Advanced Unresectable/Metastatic Solid Tumors, Refractory to Standard Therapies
Official Title
A Phase I-II, First-in-Human Study of SKB264 in Patients With Locally Advanced Unresectable /Metastatic Solid Tumors Who Are Refractory to Available Standard Therapies
Brief Summary
A Phase I-II, First-in-Human Study of SKB264 in Patients with Locally Advanced
Unresectable/Metastatic Solid Tumors who are refractory to Available Standard Therapies.
Patient must have historically documented, incurable, locally advanced or metastatic cancer
that are refractory to standard therapies of one of the following types:
1. Triple negative breast cancer
2. Epithelial ovarian cancer
3. Non-small cell lung cancer
4. Gastric adenocarcinoma/Gastroesophageal junction adenocarcinoma
5. Small cell lung cancer
6. HR+/ HER2-breast cancer
7. Head and neck squamous cell carcinoma
8. Endometrial carcinoma
9. Urothelial carcinoma
Detailed Description
This is an open label, Phase I-II, first in human (FIH) study for SKB264 as monotherapy in
patients who have locally advanced unresectable or metastatic solid tumor that is refractory
to all standard therapies. TROP2 (trophoblast antigen 2) assessments will not be performed
prior to enrollment but it will be assessed retrospectively. Confirmation of TROP2
(trophoblast antigen 2) expression by immunohistology or other means is not required, but the
Sponsor will request fresh tumor biopsy or tissue specimens from archived materials for
determination of TROP2 (trophoblast antigen 2) expression retrospectively. The patient must
be, in the judgment of the investigator, an appropriate candidate for experimental therapy
whose tumor is refractory to standard therapies. Patients will receive study drug as a single
IV infusion at the prescribed dose level at each administration. Cycles will continue until
disease progression or unacceptable toxicity. The study is divided into 2 parts (Phase I and
Phase II).
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Phase I: Maximum Tolerated Dose (MTD) and Recommended Doses for Expansion (RDEs)
Secondary Outcome
Phase I: Dose Limiting Toxicities (DLTs)
Condition
Epithelial Ovarian Cancer
Intervention
SKB264
Study Arms / Comparison Groups
Phase I: Dose Escalation
Description: Five dose levels have been selected for evaluation in the Phase I part of the study: 2, 4, 6, 9, and 12 mg/kg of SKB264
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
430
Start Date
February 28, 2020
Completion Date
December 2025
Primary Completion Date
November 2024
Eligibility Criteria
Diagnosis and Main Criteria for Inclusion:
Inclusion Criteria:
Patients must meet the following criteria for inclusion into the study:
Phase I:
1. Patients must be able to provide documented voluntary informed consent.
2. Male or female patient aged 18-75 years.
3. Histologically documented, incurable, locally advanced or metastatic epithelial origin
malignant cancer, priority to include but not limited to the following tumor types:
Breast cancer Ovarian epithelial cancer Non-small cell lung cancer Gastric
adenocarcinoma Small cell lung cancer Urothelial carcinoma Note: Confirmation of TROP2
expression by immunohistology or other means is not required, but the Sponsor will
request tissue specimens from fresh or archived materials for determination of TROP2
expression.
4. Measurable disease by CT/MRI during dose escalation.
5. Patients should have an unresectable locally advanced or metastatic solid tumor that
is refractory to standard therapies, or have no standard therapies, or standard
treatment is not applicable at this stage.
6. Granulocyte count ≥ 1.5×109/L, platelet count ≥ 100×109/L, and hemoglobin ≥ 9 g/dL.
7. International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
≤ 1.5×ULN.
8. Serum bilirubin ≤ 1.5 mg/dL (Patients with known Gilbert disease who have serum
bilirubin level ≤ 3 ×ULN may be enrolled)., aspartate aminotransferase (AST), alanine
aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN),
with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and
patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN).
9. Creatinine clearance ≥ 50 mL/min calculated by Cockcroft-Gault, Chronic Kidney Disease
Epidemiology Collaboration, or Modification of Diet in Renal Disease formulas. Note
that 24 hour urine collection is not required but is allowed.
10. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
11. For female patients of childbearing potential and male patients with partners of
childbearing potential, agreement (by patient and/or partner) to use a highly
effective form(s) of contraception during study treatment. Female and male patient
treated with SKB264 should continue contraception use for 7 months after the last
dose. Such methods include combined (estrogen and progestogen containing) hormonal
contraception, progestogen-only hormonal contraception associated with inhibition of
ovulation together with another additional barrier method always containing a
spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS),
bilateral tubal occlusion or vasectomized partner (on the understanding that this is
the only one partner during the whole study duration), and sexual abstinence.
- Oral contraception should always be combined with an additional contraceptive
method because of a potential interaction with the study drug. The same rules are
valid for male patients involved in this clinical trial if they have a partner of
childbirth potential. Male patients must always use a condom.
- Women are excluded from birth control if they had had tubal ligation or a
hysterectomy.
12. Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute
toxicities from previous therapy, excluding alopecia and vitiligo.
13. Expected survival ≥ 3 months.
Phase II:
1. Patients must be able to provide documented voluntary informed consent.
2. Male or female patient aged ≥ 18 years.
3. Histologically or cytologically documented, incurable, locally advanced, recurrent or
metastatic cancer, priority to include but not limited to the following tumor types
(the sponsor will add or remove indications based on real-time study results):
Triple negative breast cancer Epithelial ovarian cancer Non-small cell lung cancer
(For Cohort 3B, only EGFR wild-type NSCLC will be enrolled) Gastric adenocarcinoma or
gastroesophageal junction adenocarcinoma (gastroesophageal junction adenocarcinoma is
defined as tumor with center located within 5cm below/above the anatomical
esophagogastric junction per Siewert classification system) Small cell lung cancer
HR+/ HER2- breast cancer Head and neck squamous cell carcinoma (including primary
tumor location of oropharynx, oral cavity, hypopharynx, or larynx. Other primary tumor
sites of HNSCC, including nasopharynx (any histology) or unknown primary tumor are not
eligible) Endometrial carcinoma (including carcinosarcoma, but except sarcoma and
neuroendocrine endometrial carcinoma) Urothelial carcinoma (including urothelial
carcinoma of the renal pelvis, ureter, bladder, or urethra, patients with mixed
histology are eligible provided urothelial component > 50% and plasmacytoid
component<10% (Pathology will be locally assessed), patients whose tumors contain any
neuroendocrine component are not eligible) Note: Confirmation of TROP2 expression by
immunohistology or other means is not required, but the Sponsor will request tissue
specimens from fresh or archived materials for determination of Trop-2 expression.
4. Measurable disease by CT/MRI.
5. For Cohort 1, 2, 3A, patients should have an unresectable locally advanced or
metastatic solid tumor that is refractory to standard therapies, or have no standard
therapies, or standard treatment is not applicable at this stage. For other cohorts,
prior lines of therapy as below:
Cohort 3B: EGFR wild-type NSCLC: Patients have received platinum-containing
chemotherapy in combination with anti-PD-1/L1 monoclonal antibodies as the only prior
line of therapy; Prior neoadjuvant and/or adjuvant system therapy/ radical
chemoradiotherapy would be counted as a line of therapy if the patient progressed to
unresectable locally advanced, recurrent or metastatic disease during or within 6
months of completing neoadjuvant or adjuvant therapy.
Cohort 4: GC or GEJC: Patients who have been treated with only one prior therapy of
chemotherapy and anti-PD-1/L1 monoclonal antibodies therapy and progressed during or
after treatment. Prior neoadjuvant and/or adjuvant system therapy would be counted as
a line of therapy if the patient progressed to unresectable locally advanced,
recurrent or metastatic disease during or within 6 months of completing neoadjuvant or
adjuvant therapy.
Cohort 5: Second-line ES-SCLC: Patients who must have progressed on or after treatment
with an anti-PD-1/L1 monoclonal antibodies administrated as part of first-line
platinum-based systemic therapy for ES-SCLC. Previously treated limited stage SCLC
will not be eligible.
Cohort 6: HR+/ HER2-BC : Patients who have received previously at least two and no
more than four lines of chemotherapy for unresectable locally advanced or metastatic
disease with at least one taxane-containing in any setting. Prior neoadjuvant and/or
adjuvant chemotherapy would be counted as a line of therapy if the patients progressed
to unresectable locally advanced, recurrent or metastatic disease during or within 12
months of completing neoadjuvant or adjuvant therapy. Patients should also have
previously presented a progression on anticancer hormonal therapy with a CDK 4/6
inhibitor and/ or a relapse during or after adjuvant endocrine therapy combined with
an approved CDK4/6 inhibitor in this setting. Note: 1) Patients with HR+/HER2-BC and
visceral crisis will be excluded. 2) For patients who have known BRCA mutation and
HR+/HER2-BC, prior PARP inhibitor is required before enrolled in this study (where
available and not medically contraindicated). 3) For patients with unknown BRCA
status, prior PARP inhibitor is not required. 4) Patients who previously received
therapy with an anti- HER2 ADC (T-Dxd) for HER2 low expressing tumors are eligible and
this therapy will count as one chemotherapy line for unresectable locally advanced or
metastatic disease.
Cohort 7: HNSCC: Patients who have been previously treated with therapy of
anti-PD-1/L1 monoclonal antibodies (either as a single-agent or in combination with
platinum-based chemotherapy) as first-line treatment in recurrent/metastatic (R/M)
setting and progressed during or after treatment. Prior definitive/multimodal therapy
for locally advanced (LA) HNSCC that included anti-PD-1/PD-L1 monoclonal antibodies
and platinum therapy would be counted as a line of therapy if the patient progressed
during or within 6 months of completing definitive therapy.
Cohort 8: Endometrial cancer: Patients who have previously failed with first-line
platinum-based chemotherapy; patients with microsatellite stability/non-mismatch
repair deficiency (MSS/pMMR) endometrial carcinoma must have received prior
platinum-based therapy and progressed during or after treatment. Patients with known
high microsatellite instability/mismatch repair deficiency (MSI-H/dMMR) endometrial
carcinoma must have received prior platinum-based therapy and anti-PD-1/L1 monoclonal
antibodies therapy and progressed during or after treatment. Prior
neoadjuvant/adjuvant chemotherapy would be counted as a line of therapy if the patient
progressed to unresectable locally advanced, recurrent or metastatic disease during or
within 12 months of completing neoadjuvant or adjuvant therapy. Note: 1) If
anti-PD-1/L1 monoclonal antibodies therapy is not approved for second-line treatment
for MSI-H/dMMR endometrial cancer patients in certain regions, prior treatment with
anti-PD-1/L1 monoclonal antibodies is not required. 2) If MMR/MSI status is unknown,
patients who have been only treated with platinum based therapy is acceptable.
Cohort 9: UC: Patients who have failed with prior first-line platinum-based therapy
and received prior anti-PD-1/L1 monoclonal antibodies therapy and progressed during or
after the latest treatment. Prior neoadjuvant/adjuvant system therapy would be counted
as a line of therapy if the patient progressed to unresectable locally advanced,
recurrent or metastatic disease during or within 12 months after completing
neoadjuvant or adjuvant therapy.
6. Granulocyte count ≥ 1.5×109/L, platelet count ≥ 100×109/L, and hemoglobin ≥ 9 g/dL.
7. International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
≤ 1.5×ULN.
8. Serum bilirubin ≤ 1.5 mg/dL (Patients with known Gilbert disease who have serum
bilirubin level ≤ 3 ×ULN may be enrolled), aspartate aminotransferase (AST), alanine
aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN),
with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and
patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN).
9. Creatinine clearance ≥ 50 mL/min calculated by Cockcroft-Gault, Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI), or Modification of Diet in Renal Disease (MDRD)
formulas. Note that 24 hour urine collection is not required but is allowed.
10. ECOG Performance Status 0 or 1.
11. For female patients of childbearing potential and male patients with partners of
childbearing potential, agreement (by patient and/or partner) to use a highly
effective form(s) of contraception during study treatment. Female and male patient
treated with SKB264 should continue contraception use for 6 months after the last
dose. Such methods include combined (estrogen and progestogen containing) hormonal
contraception, progestogen-only hormonal contraception associated with inhibition of
ovulation together with another additional barrier method always containing a
spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS),
bilateral tubal occlusion or vasectomized partner (on the understanding that this is
the only one partner during the whole study duration), and sexual abstinence.
- Oral contraception should always be combined with an additional contraceptive
method because of a potential interaction with the study drug. The same rules are
valid for male patients involved in this clinical trial if they have a partner of
childbirth potential. Male patients must always use a condom.
- Women are excluded from birth control if they had had tubal ligation or a
hysterectomy.
12. Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute
toxicities from previous therapy, excluding alopecia and vitiligo. Note: Subjects with
endocrine AE of any grade are permitted to enroll if they are stably maintained on
appropriate replacement therapy and are asymptomatic.
13. Expected survival ≥ 3 months.
Exclusion Criteria:
Patients that meet the following criteria will be excluded from entry into the study:
Phase I:
1. Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure
(New York Heart Association) III or IV, unstable angina pectoris even if medically
controlled, history of myocardial infarction during the last 6 months, serious
arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal
supraventricular tachycardia).
2. Symptomatic brain metastases or any radiation or surgery for brain metastases within 1
months of first infusion of study drug.
3. Subjects with second primary cancers (except for cured in situ non-melanoma skin
cancer and in situ cervical cancer with no relapse in the last 3 years).
4. Require supplemental oxygen for daily activities.
5. Documented Grade ≥ 2 peripheral neuropathy.
6. History of documented severe dry eye syndrome, severe Meibomian gland disease and/or
blepharitis, corneal disease that prevents/delays corneal healing, macular
degeneration.
7. Subjects previously treated with TROP 2 targeted therapies.
8. Any standard cancer therapy (e.g. chemotherapy, hormonal therapy, radiotherapy,
immunotherapy, biologic therapy treatment, or therapy with traditional Chinese
medicines approved for anti-tumor treatment, etc.) within 4 weeks or five half-lives,
whichever is shorter, of first infusion of study drug.
9. Any experimental therapy within 4 weeks or five half-lives, whichever is shorter, of
first infusion of study drug.
10. Any major surgical procedure within 4 weeks of first infusion of study drug.
11. Diagnosed active liver disease, including viral or other hepatitis, current or history
of alcoholism, or cirrhosis.
12. Have known prior positive test results or medical history for human immunodeficiency
virus.
13. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood
pressure ≥ 100 mmHg) or diabetes (HbA1c ≥ 9.0%).
14. Subjects who require use of strong inhibitors or inducers of CYP3A4 at least 14 days
prior to and throughout Study. Use of strong inhibitors or inducers of CYP3A4 is not
allowed in this study. List of representative examples of strong inhibitors or
inducers of CYP3A4 is provided in Appendix III.
15. Pregnancy or lactation.
16. Left ventricular ejection fraction < 45% determined by echocardiogram or multiple
gated acquisition scan.
17. Resting QTc > 480 msec at baseline.
18. Ascites requiring paracentesis ≥1 per week.
19. Symptomatic pleural effusion (< 90% oxygen saturation).
20. Subjects with non-infectious interstitial lung diseases (ILD) or medical history of
pneumonia requiring steroid treatments; severe pulmonary dysfunction caused by lung
diseases.
21. New diagnosed thromboembolic events that requires therapeutic intervention over the
last 6 months (patients with stable control of lower limb deep venous thrombosis are
allowed).
22. The investigator considers other situations that patients are not appropriate to
participate in this trial.
Phase II:
1. Any patient who was treated in the Phase I part of this study.
2. Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure
(New York Heart Association) III or IV, unstable angina pectoris even if medically
controlled, history of myocardial infarction during the last 6 months, serious
arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal
supraventricular tachycardia).
3. Symptomatic brain metastases or any radiation or surgery for brain metastases within 1
months of first infusion of study drug.
4. Patients with active second primary cancers (except for cured in situ non-melanoma
skin cancer and in situ cervical cancer with no relapse in the last 3 years, or other
malignant cancers that have been cured and no evidence of recurrence).
5. Require supplemental oxygen for daily activities.
6. Documented Grade ≥ 2 peripheral neuropathy.
7. History of documented severe dry eye syndrome, severe Meibomian gland disease and/or
blepharitis, corneal disease that prevents/delays corneal healing, macular
degeneration.
8. Patients previously treated with TROP 2 targeted therapies or topoisomerase
I-containing antibody drug conjugates at any time for early stage or metastatic
disease.
9. Any standard cancer therapy (e.g. chemotherapy, hormonal therapy, radiotherapy,
immunotherapy, biologic therapy treatment, or therapy with traditional Chinese
medicines approved for anti-tumor treatment, etc.) within 4 weeks or 5 half-lives,
whichever is shorter, of first infusion of study drug.
10. Any experimental therapy within 4 weeks or 5 half-lives, whichever is shorter, of
first infusion of study drug.
11. Any major surgical procedure within 4 weeks of first infusion of study drug.
12. Diagnosed active liver disease, including viral or other hepatitis, current or history
of alcoholism, or cirrhosis.
13. Have known prior positive test results or medical history for human immunodeficiency
virus.
14. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood
pressure ≥ 100 mmHg) or diabetes (HbA1c ≥ 9.0%).
15. Subjects who require use of strong inhibitors or inducers of CYP3A4 at least 14 days
prior to and throughout Study. Use of strong inhibitors or inducers of CYP3A4 is not
allowed in this Study. List of representative examples of strong inhibitors or
inducers of CYP3A4 is provided in Appendix III.
16. Pregnancy or lactation.
17. Left ventricular ejection fraction < 45% determined by echocardiogram or multiple
gated acquisition scan.
18. Resting QTcF > 480 msec at baseline.
19. Ascites requiring paracentesis >1 per week.
20. Symptomatic pleural effusion (< 90% oxygen saturation).
21. History of interstitial lung diseases (ILD) or non-infectious pneumonitis requiring
steroid treatments; severe pulmonary dysfunction caused by lung diseases.
22. New diagnosed thromboembolic events that requires therapeutic intervention over the
last 6 months (patients with stable control of lower limb deep venous thrombosis are
allowed).
23. The investigator considers other situations that patients are not appropriate to
participate in this trial.
Gender
All
Ages
18 Years - 75 Years
Accepts Healthy Volunteers
No
Contacts
Jordi Rodon Ahnert, MD, PhD, +1 416-471-1960, [email protected]
Location Countries
China
Location Countries
China
Administrative Informations
NCT ID
NCT04152499
Organization ID
KL264-01
Responsible Party
Sponsor
Study Sponsor
Klus Pharma Inc.
Study Sponsor
Jordi Rodon Ahnert, MD, PhD, Study Chair, M.D. Anderson Cancer Center
Verification Date
November 2022