IN10018 Monotherapy and Combination Therapy for Metastatic Melanoma

• ClinicalTrials.gov Identifier: NCT04109456
• Recruitment Status: Recruiting
• First Posted: September 30, 2019
• Last Update Posted: January 10, 2024
• Sponsor: InxMed (Shanghai) Co., Ltd.
• Information provided by (Responsible Party): InxMed (Shanghai) Co., Ltd.

Study Description

Brief Summary:

This is a phase Ib, open label clinical study to evaluate the safety, tolerability, PK and antitumor activities of IN10018 as monotherapy and in combination with cobimetinib in subjects with metastatic uveal melanoma and NRAS-mutant metastatic melanoma.

Condition or disease	Intervention/treatment	Phase
Metastatic Melanoma	Drug: IN10018; Drug: Cobimetinib; Biological: Atezolizumab	Phase 1

Detailed Description:

Subjects with metastatic uveal melanoma (UM) or with NRAS-mutant metastatic melanoma will be enrolled.

IN10018 will be assessed firstly as monotherapy（Part 1）, then in combination with cobimetinib (Part 2) and in combination with cobimetinib and Atezolizumab (Part 3).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

The safety and tolerability of IN10018 monotherapy (Part 1) will be assessed firstly. Other dose levels may be explored if necessary.

and then the safety and tolerability of IN10018 in combination with Cobimetinib (Part 2) will be evaluated.

the safety and tolerability of IN10018 in combination with Cobimetinib and Atezolizumab (Part 3) will be evaluated .

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib, Open-label Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Antitumor Activities of IN10018 as Monotherapy and Combination Therapy in Subjects With Metastatic Melanoma
• Actual Study Start Date: March 16, 2020
• Estimated Primary Completion Date: June 30, 2024
• Estimated Study Completion Date: September 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1, Monotherapy Arm; The safety and tolerability of IN10018 monotherapy will be assessed. Other dose levels may be explored if necessary.	Drug: IN10018; 100 mg or 50mg, orally once daily continuously; Other Name: BI 853520
Experimental: Part 2, Combination Arm; The safety and tolerability of IN10018 in combination with Cobimetinib will be assessed. Other dose levels may be explored if necessary. A modified 3+3 design will be used.	Drug: IN10018; 100 mg or 50mg, orally once daily continuously; Other Name: BI 853520; Drug: Cobimetinib; 60mg , orally once daily from day 1 to day 21 in a 28-day cycle; Other Name: Cotellic
Experimental: Part 3, Combination Arm; The safety and tolerability of IN10018 in combination with Cobimetinib and Atezolizumab will be assessed.	Drug: IN10018; 100 mg or 50mg, orally once daily continuously; Other Name: BI 853520; Drug: Cobimetinib; 60mg , orally once daily from day 1 to day 21 in a 28-day cycle; Other Name: Cotellic; Biological: Atezolizumab; biweekly 840 mg dose will be used in this study starting from Cycle 2.

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability of IN10018 monotherapy [ Time Frame: The first 21-day cycle ]
   Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
2. Safety and tolerability of IN10018 in combination with cobimetinib [ Time Frame: The first 28-day cycle ]
   Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
3. Safety and tolerability of IN10018 in combination with cobimetinib and atezolizumab [ Time Frame: All treatment period ]
   Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment

Secondary Outcome Measures :

1. Pharmacokinetics (PK) : Cmax [ Time Frame: Cycle 1 and Cycle 3 ]
   Peak Plasma Concentration (Cmax)
2. Pharmacokinetics (PK) : AUC [ Time Frame: Cycle 1 and Cycle 3 ]
   Area under the plasma concentration versus time curve (AUC)
3. Pharmacokinetics (PK) : tmax [ Time Frame: Cycle 1 and Cycle 3 ]
   Time to Cmax (tmax)
4. Pharmacokinetics (PK) : t1/2 [ Time Frame: Cycle 1 and Cycle 3 ]
   Elimination half-life (t1/2)
5. Pharmacokinetics (PK) : CL/F [ Time Frame: Cycle 1 and Cycle 3 ]
   apparent clearance (CL/F)
6. Pharmacokinetics (PK) : Vd [ Time Frame: Cycle 1 and Cycle 3 ]
   Apparent volume of distribution(Vd)
7. Overall Response Rates using RECiST1.1 criteria [ Time Frame: 1 year ]
   Proportion of participants with (complete response, partial response, stable disease, progressive disease) in all 3 parts
8. Disease Control Rate using RECiST1.1 criteria [ Time Frame: 1 year ]
   Proportion of subjects who have disease control (CR, PR or stable disease (SD)) in all 3 parts
9. duration of response (DOR) [ Time Frame: 1 year ]
   For subjects who demonstrate CR or PR, DOR is defined as the time from first evidence of CR or PR until PD or death due to any cause, whichever occurs first in all 3 parts
10. progression free survival (PFS) [ Time Frame: 1 year ]
    PFS is defined as the time from the first day of study treatment to the first disease progression or death due to any cause, whichever occurs first in all 3 parts
11. overall survival (OS) [ Time Frame: 1 year ]
    OS is defined as the time from the first day of study treatment to death due to any cause in all 3 parts

Other Outcome Measures:

1. To explore potential predictive biomarkers [ Time Frame: through study completion, an average of 5 year ]
   in all 3 parts

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

1. Ability to understand and willingness to sign informed consent(s).
2. Male or female subjects ≥ 18 years at the time of signing informed consent.

3. Histologically or cytologically confirmed metastatic melanoma with subtypes limited to:

   1. Metastatic uveal melanoma, or
   2. Metastatic NRAS-mutant melanoma harboring an NRAS activating mutations of Q61, G12, or G13 mutation per local laboratory (including local reference laboratory) results.

4. Requirements for previous therapy:

   1. Uveal melanoma: Either be treatment naïve or have failed the most recent therapy for metastatic disease, or
   2. NRAS-mutant melanoma: Either be ineligible for standard of care due to the presence of various comorbidities or have failed the most recent therapy such as immunotherapy for metastatic disease.
   3. Have failed immunotherapy therapy (anti-PD-1 or anti-PD-L1) alone or in combination with other agents for metastatic disease either with no initial response or disease progression after an initial response. (Part 3)
   4. Received a minimum of two cycles of anti-PD-1/PD-L1 therapy. (Part 3)
5. Consent to undergo tumor biopsies of accessible lesions, before and during treatment and at radiographic progression, for biomarker analyses (site dependent).
6. At least one measurable lesion can be accurately measured per RECIST 1.1 by investigator.
7. ECOG performance status of 0 or 1.
8. Life expectancy of at least 3 months as assessed by investigator.
9. Availability of fresh tumor tissue and/or archival tumor tissue at Screening if agreed by subjects.
10. Must have recovered from all AEs due to previous therapies to ≤ Grade 1 (CTCAE 5.0) or stable status as assessed by investigator.
11. Adequate bone marrow, liver, renal, and coagulation function within 5 days prior to first dose of study treatment.
12. A male subject must agree to use contraception as detailed in Appendix 4 of this protocol during the treatment period and through 30 days after the last dose of study treatment and must refrain from donating sperm during this period.

13. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:

    1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 4. OR
    2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during the treatment period and through 30 days after the last dose of study treatment.

Key Exclusion Criteria:

1. Has had major surgery or significant traumatic injury within 28 days prior to first dose of study treatment, or anticipation of the need for major surgery during study treatment.
2. Has received prior systemic, intrahepatic, or sphere anticancer therapy including investigational agents within 14 days or less than 5 half-lives (whichever is shorter) of chemotherapy or targeted therapy, or within 28 days of immunotherapy, prior to first dose of study treatment.
3. Has received prior radiotherapy or radioactive chemotherapy within 14 days prior to first dose of study treatment.
4. Has received prior treatment of any FAK inhibitor (Parts 1, 2 and 3), or prior treatment of any MEK inhibitor (Parts 2 and 3 only).
5. Has a known previous or concurrent cancer that is distinct in primary site or histology from current melanoma within 3 years prior to first dose of study treatment, except for curatively treated cancers such as cervical carcinoma in situ and indolent cancers with very low likelihood of relapse or progress per investigator judgement.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
7. Diabetes mellitus, insulin dependent and non-insulin dependent with HBA1C > 6.5%, microalbuminuria > 150 mg (24-h collection), and CrCL of < 45ml/min with an adequate 24-hour urine collection.
8. Prior history of Alport syndrome.
9. Recent medical history (with the last 1-year) of acute renal injury, Goodpasture's Syndrome, IgA nephropathy, focal segmental glomerulosclerosis, nephrotic syndrome, parenteral drug abuse, recurrent pyelonephritis, systemic lupus erythematosus, uncontrolled hypertension, vasculitis, and chronic illnesses with potential underlying glomerular renal disease.
10. Has contraindications to anti-PD-1 or anti-PD-L1 immunotherapy (Part 3).
11. Has received prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA4 immunotherapy and was discontinued for significant immunotherapy-related adverse events (Part 3).
12. Current treatment with anti-viral therapy for HBV (Part 3).
13. Prior allogeneic stem cell or solid organ transplantation.
14. Active tuberculosis
15. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina (Part 3).
16. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study. (Part 3).
17. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on previous chest computed tomography (CT) scan.

18. Has a history of major cardiovascular, cerebrovascular, or thromboembolic diseases (e.g., congestive heart failure, acute myocardial infarction, unstable angina, atrial fibrillation, ventricular tachyarrhythmia, uncontrolled hypertension, stroke, transient ischemic attack, deep vein thrombosis or pulmonary embolism) within 6 months before first dose of study treatment, or has any of the following abnormality:

    • QTc interval > 480 msec (Fridericia formula), (patients with right bundle branch block is not required to have QTc if the block is stable and assessed as not clinically significant by the PI),
    • Left ventricular ejection fraction (LVEF) < 50%,
    • Arrhythmia with clinical significance, or
    • Other heart diseases with clinical significance.
19. History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/ central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), neovascular macular degeneration, or uncontrolled glaucoma with intra-ocular pressures >21 mmHg in the eye(s) unaffected by melanoma. (Parts 2 and 3)
20. Has known uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage prior to the first dose of study treatment.
21. Has malabsorption syndrome or inability to take oral drugs.
22. Has clinically significant gastrointestinal abnormalities including uncontrolled gastrointestinal inflammatory lesions (Crohn's disease, or ulcerative colitis in active or uncontrolled gastrointestinal bleeding).
23. Known allergy or hypersensitivity to IN10018 cobimetinib and/or atezolizumab, or their ingredients.
24. Has had an active infection requiring systemic therapy within 14 days prior to the first dose of study treatment.
25. Has known human immunodeficiency virus (HIV) infection.
26. Has known active Hepatitis B or Hepatitis C virus infection.
27. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
28. Has a known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the study.

29. Has had used below CYP3A inhibitors/inducers and P-gp inhibitors within 14 days prior to first dose of study treatment, or anticipation of the need to use them during study treatment:

    • Part 1: Strong CYP3A inhibitors/inducers and P-gp inhibitors are prohibited at least 14 days prior to initiation of and during study treatment.
    • Parts 2 and 3: Moderate and Strong CYP3A inhibitors/inducers and P-gp inhibitors are prohibited at least 14 days prior to initiation of and during study treatment.

Contacts and Locations

Contacts

Contact: Eddie Xing, Dr.; 9495200786; eddie.xing@inxmed.com

Locations

United States, Florida

Sylvester Comprehensive Cancer Center.; Recruiting

Miami, Florida, United States, 33136

Contact: Lynn Feun, Dr. 305-243-4981 lfeun@miami.edu

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Ryan Sullivan, MD 617-724-4000 RSULLIVAN7@PARTNERS.ORG

Dana-Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Rizwan Haq, PhD. 617-632-5055 Rizwan_haq@dfci.harvard.edu

United States, New York

Columbia University Medical Center; Recruiting

New York, New York, United States, 10032

Contact: Rachard Carvajal, Dr. rdc2150@cumc.columbia.edu

United States, Texas

MD Anderson; Recruiting

Houston, Texas, United States, 77030

Contact: Sapna Patel 713-792-2921 melanoma@mdanderson.org.org

Principal Investigator: Sapna Patel

Australia, New South Wales

St Vincent Hospital Sydney; Recruiting

Sydney, New South Wales, Australia

Contact: Anthony Joshua, MD

Contact: Arvin Caraos (02)9355 5706 arvin.caraos@svha.org.au

Australia, Victoria

The Alfred Hospital; Recruiting

Melbourne, Victoria, Australia

Contact: Mark Shackleton

Contact: Anne Everts 03 9076 0566 A.Everts@alfred.org.au

Australia, Western Australia

Linear Clinical Research; Recruiting

Nedlands, Western Australia, Australia

Contact: Michal Millward, MD

Contact: Kyle Summers (08) 6382 5115 cancertrialsONC1@linear.org.au

Sponsors and Collaborators

InxMed (Shanghai) Co., Ltd.

Investigators

• Study Director: Eddie Xing, Dr.; InxMed Shanghai

More Information

• Responsible Party: InxMed (Shanghai) Co., Ltd.
• ClinicalTrials.gov Identifier: NCT04109456
• Other Study ID Numbers: IN10018-004-01
• First Posted: September 30, 2019
• Last Update Posted: January 10, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by InxMed (Shanghai) Co., Ltd.:

uveal; NRAS

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Atezolizumab; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Antineoplastic Agents