Safety, Tolerability and Pharmacokinetics Study of KPG-818 in Hematological Malignancies Subjects

• ClinicalTrials.gov Identifier: NCT04283097
• Recruitment Status: Recruiting
• First Posted: February 25, 2020
• Last Update Posted: February 22, 2023
• Sponsor: Kangpu Biopharmaceuticals, Ltd.
• Information provided by (Responsible Party): Kangpu Biopharmaceuticals, Ltd.

Tracking Information

• First Submitted Date: February 21, 2020
• First Posted Date: February 25, 2020
• Last Update Posted Date: February 22, 2023
• Actual Study Start Date: May 15, 2020
• Estimated Primary Completion Date: August 30, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 21, 2020)

• Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Up to 6 months of treatment ]
  Number of Treatment-Emergent Adverse Events(TEAE), serious adverse events (SAEs), dose-limiting toxicities (DLTs), and changes from baseline in laboratory parameters, vital signs, and ECG.
• Recommended Phase 2 Dose (RP2D) [ Time Frame: Up to 28-day of treatment ]
  Maximum tolerated dose defined as the highest dose level at which 33% or less subjects experience DLT as defined by the protocol.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 21, 2020)

• PK profile of KPG-818 [ Time Frame: Up to 28-day of treatment ]
  Cmax, time of the maximum observed plasma concentration (Tmax), AUC0-t, AUC from time zero extrapolated to infinity (AUC0-∞), AUC within a dosing interval (AUC0-τ), apparent total plasma clearance (CL/F), apparent total plasma clearance at steady-state (CLss/F), apparent volume of distribution (Vz/F), apparent volume of distribution at steady-state (Vss/F), and t1/2.
• Preliminary clinical activity [ Time Frame: Up to 6 months of treatment ]
  Objective response rate (ORR), disease control rate (DCR), time to response, duration of response (DOR), progression-free survival (PFS), event-free survival (EFS), and transplantation rate (TR). Responses are evaluated based on International Myeloma Working Group (IMWG) Uniform Response Criteria (for MM), Lugano Classification 3 (for lymphoma), International Workshop Group on CLL (iwCLL) Response Criteria, and according to the Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia lymphoma (ATL).

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: February 21, 2020)

Biomarkers of KPG-818 [ Time Frame: Up to 6 months of treatment ]

Aiolos and Ikaros in peripheral blood mononuclear cell (PBMC)

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Safety, Tolerability and Pharmacokinetics Study of KPG-818 in Hematological Malignancies Subjects
• Official Title: A Phase 1, Multicenter, Open-label, Multiple-ascending Dose Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of KPG-818 in Subjects With Hematological Malignancies

Brief Summary

This is a Phase 1, multicenter, open-label, multiple-ascending dose study to evaluate the safety, PK, and preliminary clinical activity of KPG-818 in combination with dexamethasone in adult subjects with multiple myeloma (MM), and KPG-818 as monotherapy in subjects with other selected hematological malignancies, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), adult T-cell leukemia lymphoma (ATL), indolent lymphoma, such as follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), etc.

This study will assist in identifying appropriate, well tolerated doses that can be administered in subsequent studies in subjects with selected hematological malignancies.

Detailed Description

This is a Phase 1, multicenter, open-label, multiple-ascending dose study to evaluate the safety, PK, and preliminary clinical activity of KPG-818 in combination with dexamethasone in adult subjects with multiple myeloma (MM), and KPG-818 as monotherapy in subjects with other selected hematological malignancies, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), adult T-cell leukemia lymphoma (ATL), indolent lymphoma, such as follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), etc.

This will be a dose escalation study in subjects with selected hematological malignancies. All study center(s) will be in the US.

After providing informed consent, subjects will be assessed for study eligibility at the Screening visit (Days -28 to -1). Cohorts of 1 to 6 subjects per dose level will be given escalating doses of KPG-818 during each 28-day cycle orally until progressive disease (PD), unacceptable toxicity, the subject withdraws, or any other study withdrawal criterion is met. The 4 planned dose escalation cohorts will be 5, 10, 20, and 30 mg. The highest does level which may be tested is 30mg. If there are safety concerns, dose level or dosing schedule may be modified and recommended by SRC.

Dose escalation will use an accelerated titration design (ATD) where the first dose level will include one subject. Subsequent dose levels will use a 3+3 approach to establish a MTD. The first subject will receive the initial escalation dose level 5 mg/day and be dosed according to specific dosing schedule over a 28-day treatment cycle, and in the absence of a DLT or Grade 2 or greater study drug-related AE and after review of the data from the first full cycle by the Safety Review Committee (SRC), the next 3 subjects will receive 10 mg/day followed by review of the data by the SRC. Once 10 mg/day is reached, the enrolment will revert to a standard 3+3 escalation design.

If 1 or more Grade 2 or greater study drug-related AE is observed at dose level 5 mg/day, two additional subjects will be enrolled at the same dose level, and dose escalation reverts to a standard 3+3 escalation design. If 1 or more DLT is observed at dose level 5 mg/day, five additional subjects will be enrolled at the same dose level and dose escalation reverts to a standard 3+3 escalation design . Enrolment to 10 mg/day will follow a standard 3+3 escalation design.

Dose-limiting toxicity (DLT) will be assessed during the 28-day DLT evaluation period. Non-DLT evaluable subjects who exit the study for reasons other than DLT prior to completion of the 28-day evaluation period with a drug exposure of at least 80% of the planned doses will be replaced to ensure an adequate safety assessment at each dose.

The Safety Review Committee (SRC), will be responsible for dose escalation decisions, including whether to modify the dose escalation based on the DLT observations or determine RP2D. Escalation to the Maximal Tolerated Dose (MTD) is not appropriate if activity plateaus at a lower dose.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Dose escalation will use an accelerated titration design (ATD) in Dose Level 1 cohort where the first dose level will start with one subject only. Subsequent dose levels will use a 3+3 approach to establish a maximum tolerated dose (MTD).Dose-limiting toxicity will be assessed during the 28-day DLT evaluation period. Subjects who exit the study for reasons other than DLT prior to completion of the 28-day evaluation period will be replaced to ensure an adequate safety assessment at each dose level.

Masking: None (Open Label)
Masking Description:

This is a open label phase 1 study.

Primary Purpose: Treatment

• Condition: Hematological Malignancies

Intervention

Drug: KPG-818

KPG-818 represents a novel generation of small molecule modulators of the CRBN E3 ubiquitin ligase complex CRL4CRBN and potently induces the ubiquitination and degradation of Aiolos (IKZF3) and Ikaros (IKZF1), two members of the Ikaros family of zinc-finger transcription factors critical in B-cell development. In preclinical studies, KPG-818 demonstrated outstanding in vitro anti-inflammatory properties and broad spectrum of anti-proliferative activities as well as remarkable in vivo efficacy in animal models of multiple blood cancers.

Other Name: KPG-818 capsules

Study Arms

Experimental: KPG-818

KPG-818 dose escalation

Intervention: Drug: KPG-818

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 12, 2022): 30
• Original Estimated Enrollment (submitted: February 21, 2020): 40
• Estimated Study Completion Date: August 30, 2023
• Estimated Primary Completion Date: August 30, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

1. ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Willing and able to provide written consent.
3. Willing and able to adhere to the study visit schedule and other protocol requirements.
4. Hematocytological or pathological diagnosis of MM, MCL, DLBCL, ATL, indolent lymphoma, such as FL and CLL/SLL, etc.

5. Subjects who have relapsed from or are refractory to ALL FDA approved therapies* known to provide clinical benefit for the specific disease, unless the subject is not eligible for the approved therapy.

   *Definition of ALL FDA approved therapies are specified as below:

   Prior treatments for MM subjects:

   • Received at least 3 prior anti-myeloma regimens including at least 2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid and an anti-CD38 antibody (induction with or without a bone marrow transplant with or without maintenance therapy is considered one regimen).
   • Refractory disease defined as disease that is nonresponsive to therapy (failure to achieve minimal response or development of progressive disease) or disease progression within 60 days from the last dose of their last myeloma therapy.

   Prior treatments for NHL subjects:

   • ATL: at least 2 prior lines of therapy containing alkylator-based chemotherapy.
   • MCL: at least 2 prior lines of therapy, including CD20 antibody and alkylator chemotherapy, and a Bruton's tyrosine kinase (BTK) inhibitor.
   • DLBCL: at least 2 prior lines of therapy, including prior CD20 antibody therapy, and has received prior autologous bone marrow transplant (or is ineligible for bone marrow transplant).
   • FL: at least 2 prior lines of therapy, including CD20 antibody therapy and alkylator chemotherapy.
   • CLL/SLL: at least 2 prior lines of therapy for CLL/SLL and require treatment by 2018 iwCLL criteria.
   • Other indolent NHL: Subjects must have been treated with all standard of care therapies available to the subject which, in the assessment of the investigator, may be beneficial to the subject.

6. Have measurable or assessable disease.

   For MM:

   • M-protein quantities ≥ 0.5 g/dL by serum protein electrophoresis (SPEP or SIFE) or
   • M-protein quantities ≥ 200 mg/24-hour urine collection by urine protein electrophoresis (UPEP or UIFE) or
   • Serum free light chain (FLC) levels > 100 mg/L involved light chain and an abnormal kappa/lambda (κ/λ) ratio in subjects without detectable serum or urine M-protein or
   • For subjects with immunoglobulin (Ig) class A (IgA) myeloma whose disease can only be reliably measured by quantitative Ig measurement, a serum IgA level ≥ 0.50 g/dL.

   For MCL, DLBCL, ATL, indolent lymphoma, such as FL and CLL/SLL, etc.:

   • At least 1 bidimensionally measurable lesion larger than 1.5 cm in largest dimension by computed tomography (CT), positron emission tomography CT (PET-CT), or magnetic resonance imaging (MRI) scan.

7. Meet following laboratory requirements:

   • Absolute neutrophil count ≥ 1.0 × 109/L (Granulocyte-colony stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF] allowed if received within 2 weeks prior to screening parameter).
   • Hemoglobin > 7.5 g/dL (red blood cell [RBC] transfusion is allowed to meet eligibility if performed more than 7 days prior to screening parameter).
   • Platelet count > 75 000/μL (platelet transfusions are allowed if received more than 2 weeks prior to screening parameter)
   • Corrected serum calcium ≤ 13.5 mg/dL (≤ 3.4 mmol/L).
   • AST and/or ALT < 2.5 × ULN or < 5.0 × ULN if liver tumor is present.
   • Total serum bilirubin ≤ 1.5 × ULN.
   • Estimated serum creatinine clearance of > 60 mL/min that does not require dialysis; estimated serum creatinine clearance between 50-60 mL/min may be enrolled for KPG-818 dose ≤ 10mg/day. For subjects with serum creatinine clearance between 50-60 mL/min at screening, serum creatinine clearance levels should be monitored during the study.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. In case of ECOG 2, the Investigator can discuss with Sponsor before making eligibility decision.
9. Males and females of childbearing potential must agree to use at least two methods of contraception, as detailed in Section 6.1.3, during the study treatment and continue until 3 months after the completion of study treatment.

4.2. Exclusion Criteria

Subjects will be excluded from the study if they satisfy any of the following criteria at the Screening visit unless otherwise stated:

1. Has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Currently enrolled in another clinical study, except observational studies.
3. Has known active central nervous system metastases and/or lymphomatous meningitis.
4. Persisting toxicities related to prior anticancer treatment > Grade 1 according to NCI CTCAE v5.0.
5. Major surgery or significant traumatic injury within 6 weeks prior to Screening or planned major surgery during the study period.
6. Received live attenuated vaccine within 4 weeks of first dose.
7. Subjects with gastrointestinal disease that may significantly alter the absorption of the study drug.
8. Subjects with a plasma cell leukemia.

9. Subjects with prior history of malignancies, other than MM, lymphoma, or CLL/SLL, unless the subject has been free of the disease for ≥ 5 years with the exception of the following noninvasive malignancies:

   • Basal cell carcinoma of the skin.
   • Squamous cell carcinoma of the skin.
   • Carcinoma in situ.
   • Incidental histological findings of prostate cancer such as T1a or T1b using the tumor/node/metastasis classification of malignant tumors or prostate cancer that is curative.
10. Has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, or pomalidomide.
11. Has known or suspected hypersensitivity to the excipients contained in the formulation of investigational product (IP).

12. Has received any of the following within the last 14 days of initiating IP:

    • Plasmapheresis
    • Radiation therapy other than local therapy for MM associated bone lesions
    • Use of any systemic myeloma/lymphoma/CLL/SLL drug therapy.
13. Has been treated with an investigational agent (i.e., an agent not commercially available) within 28 days or 5 half-lives (whichever is longer) of initiating IP.
14. Prior treatment of any inhibitors of PD-1 or PD-L1 within 3 months prior to initiating IP.

15. Has any one of the following:

    • Clinically significant abnormal ECG finding, including QTcF interval elongation (> 480 ms), at Screening.
    • Congestive heart failure (New York Heart Association Class III or IV).
    • Myocardial infarction within 12 months prior to initiating IP.
    • Unstable or poorly controlled angina pectoris, including the Prinzmetal variant of angina pectoris.
    • Peripheral neuropathy ≥ Grade 2.
    • Subject has taken a strong inhibitor or inducer of CYP3A4/5 including grapefruit, St. John's Wort or related products within 2 weeks prior to dosing and during the course of study.

16. Has current or prior use of immunosuppressive medication within 14 days prior initiating IP. The following are exceptions to this criterion:

    • Intranasal, inhaled, topical, or local steroid injections (e.g., intra-articular injection)
    • Systemic corticosteroids at physiologic doses that do not exceed 10 mg/day of prednisone or equivalent
    • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).

17. Subject known to test positive for human immunodeficiency virus, active hepatitis B, or active hepatitis C.

    Note: subjects who are hepatitis B core antibody (anti-HBc) positive and hepatitis B surface antigen (HBsAg) negative are required to have a negative hepatitis B DNA PCR result before randomization and must be willing to undergo the DNA PCR testing during the study. Subjects who are HBsAg positive or hepatitis B DNA PCR positive will be excluded.

    Subjects who are hepatitis C virus antibody positive are required to have a negative hepatitis C RNA PCR result. Subjects who are hepatitis C RNA PCR-positive will be excluded.

18. Subjects with any active and uncontrolled infection.
19. Subject is unable or unwilling to undergo protocol required thromboembolism prophylaxis.
20. Subject is a female who is pregnant, nursing, or breastfeeding.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Kai Wei, MD; +8618201496205; kai.wei@kangpugroup.com

Contact: Yao Wang; yao.wang@kangpugroup.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04283097
• Other Study ID Numbers: KPG-818-HEM-101
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Kangpu Biopharmaceuticals, Ltd.
• Original Responsible Party: Same as current
• Current Study Sponsor: Kangpu Biopharmaceuticals, Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Kai Wei, MD; Kangpu Biopharmacuticals

• PRS Account: Kangpu Biopharmaceuticals, Ltd.
• Verification Date: February 2023