Details
Title A phase IB /II study of APG-115 as a monotherapy or in combination with pembrolizumab in patients with unresectable or metastatic melanomas or advanced solid tumors
IRB ACTG1Y21
CC 21-1207
Hospital Main Campus
Stage Advanced-Metastatic
Phase Phase 1, Phase 2
Disease Sarcoma
Drug APG-115 , Pembrolizumab
Description
5.1 Primary Objective
Part 1 (Phase Ib): To assess the safety and tolerability of APG-115 in combination with pembrolizumab including determination of the MTD and RP2D in patients with metastatic melanomas or solid tumors.
Part 2 (Phase II): To assess objective response rate of APG-115 in combination with pembrolizumab in the treatment of patients with unresectable or metastatic melanomas, NSCLC, solid tumors with ATM mutation, liposarcoma, urothelial carcinoma, and MPNST.
5.2 Secondary Objectives
Part 1:
1. To evaluate the pharmacokinetics profile of APG-115 in combination with pembrolizumab
2. To obtain a preliminary assessment of anti-tumor effects of APG-115 in combination with pembrolizumab in patients with advanced solid tumors
Part 2:
1. To assess the safety and tolerability of APG-115 in combination with pembrolizumab
2. To evaluate the pharmacokinetics profile of APG-115 in combination with pembrolizumab
3. To assess other anti-tumor effects of APG-115 in combination with pembrolizumab in treating the patients with metastatic melanomas, NSCLC, liposarcoma, urothelial carcinoma, solid tumors with P53 WT & ATM mutation, and MPNST.
Part 1: ORR, PFS (Progression-free survival, defined as time from the date of first dose of study treatment to the date of disease progression according to clinical or radiographic assessment or death due to any cause, whichever occurs earliest), TTR (Time to response, defined as the time from the start of treatment to the first objective tumor response observed for patients who achieved a confirmed CR or PR.) and DoR (Duration of response, will be summarized for subjects with a confirmed CR or PR and is defined as the time from date of initial confirmed response to the date of disease progression or death due to any cause) by investigator’s assessment;
Part 2: PFS, TTR, DoR by investigator’s assessment and OS (Overall survival);
• For Cohort F (MPNST), adding clinical benefit rate (CBR), defined as the percentage of subjects with a best overall confirmed CR or a PR, or a SD (≥ 4 cycles) at any time as per RECIST 1.1 and iRECIST
4. To explore potential biomarkers associated with pharmacodynamic and clinical response to APG-115 combined with pembrolizumab
To evaluate key biomarkers (via tumor biopsy and peripheral blood sample) at baseline and 14 days after administration of APG-115 in combination with pembrolizumab, and determine the relationship between key biomarkers (such as P53 status, T cell infiltration/activation) and clinical response.
Inclusion Criteria
1. Male or non-pregnant, non-lactating female patients age ≥18 years, an exception for MPNST cohort: adolescents ≥12 years old (who weigh at least 40 kg) is allowed.
2. Part 1:
a. Histologically confirmed, unresectable or metastatic melanoma, or advanced solid tumor patients who failed standard of care therapy and no further effective therapy is available
b. ECOG PS 0-2
Part 2:
For cohort A, B and E cohort, PD-1 treatment progression is defined by meeting all of the following criteria:
a. Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
b. Has demonstrated disease progression (PD) after PD-1/L1 as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than four weeks from the date of the first documented PD, in the absence of rapid clinical progression.
c. Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb.
i. Progressive disease is determined according to iRECIST or RECIST V1.1 with clinical progression.
ii. This determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression.
• Cohort A: Histologically confirmed, unresectable or metastatic melanoma, and refractory or relapse after PD-1 antibody treatment and ineligible for other standard of care therapy per NCCN guideline (previous PD-1/PD-L1 antibody treatment not required for uveal melanoma)
• Cohort B: Histologically confirmed, unresectable or metastatic NSCLC, and refractory or relapse after PD-1/PD-L1 antibody treatment and ineligible for other standard of care therapy per NCCN guideline or Histologically confirmed, unresectable or metastatic lung adenocarcinoma with STK11 mutation, and with or without previous anti-PD-1/PD-L1 antibody treatment and ineligible for other standard of care therapy per NCCN guideline
• Cohort C: Histologically confirmed, unresectable or metastatic solid tumors with P53WT and ATM mutation (including germline ATM mutation) • Cohort D: Histologically confirmed, locally advanced or metastatic well-differentiated or dedifferentiated liposarcomas who have or haven’t received prior systemic therapy (either ineligible or declining chemotherapy), and with P53 WT and MDM2 amplification
• Cohort E: Histologically confirmed, unresectable or metastatic urothelial carcinoma, and refractory or relapse after PD-1/PD-L1 antibody treatment and ineligible for other standard of care therapy per NCCN guideline
• Cohort F: Histologically confirmed, metastatic or unresectable MPNST
• Measurable disease according to RECIST 1.1. Lesions situated in a previously irradiated area, or an area subject to other loco-regional therapy (e.g., intralesional injections) should be considered non-measurable.
• ECOG PS 0-2
3. Life expectancy ≥ 3 months
4. Continuance of treatment related toxicities (except alopecia) due to prior radiotherapy or chemotherapy agents or biological therapy (including PD-1/PD-L1 antibodies) must be ≤ grade 1 at the time of dosing [G2 anemia (hemoglobin 9-10 g/dL) is an exception].
5. Adequate bone marrow and organ function as indicated by the following laboratory values without continuous supportive treatment (such as blood transfusion, coagulation factors and/or platelet infusion, red/white blood cell growth factor administration, or albumin infusion) as assessed by laboratory for eligibility:
Hematological:
• Absolute neutrophil count (ANC) ≥1.5X 109/L
• Hemoglobin ≥ 9 g/dL
• Platelet count ≥ 100 x 109/L
Coagulation:
• International normalized Ratio (INR), Prothrombin Time (PT) or Activated Partial Thromboplastin time (aPTT) ≤1.5 X ULN unless the subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
Renal:
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN);
• if serum creatinine is >1.5 X ULN, creatinine clearance must be ≥50 mL/min (see Section 22-3).
Hepatobiliary:
• Total bilirubin ≤1.5 x ULN except for subjects with Gilbert’s syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <2.5 x ULN if no evidence of liver metastases or AST and/or ALT ≤ 5.0 x ULN with liver metastases
• Alkaline phosphatase < 2.5 x ULN and < 5 x for bone metastases or hepatic parenchymal metastases on screening radiographic examination
6. QTcF interval (mean of 3, 1-3 minutes between two tests) ≤450 ms in males, and ≤470 ms in females
7. Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
8. Tumor tissue must be provided for all subjects for biomarker analysis before treatment with investigational product.
9. Willingness to use contraception by a method that is deemed effective by the investigator by both males and female patients of child-bearing potential (postmenopausal women must have been amenorrhea for at least 12 months to be considered of non-childbearing potential) and their partners throughout the treatment period and for at least three months following the last dose of study drug
10. Ability to understand and willingness to sign a written informed consent form (the consent form must be signed by the patient prior to any screening procedures). Willingness and ability to comply with study procedures and follow-up examination.
Exclusion Criteria
1. Any prior MDM2-p53 inhibitor treatment
2. Received chemotherapy within 21 days (42 days for nitrosoureas or mitomycin C) prior to first dose.
3. Part 2
Cohort A: Prior loco-regional treatment with intralesional therapy (e.g., talimogene laherparepvec) for unresectable or metastatic melanoma in the last 6 weeks prior to start of study treatment.
Cohort B: Has received radiation therapy to the lung that is >30Gy within 6 months of the first dose of trial treatment.
Cohort E: Known FGFR translocation mutation
4. Received hormonal and biologic, small molecule targeted therapies or other anti-cancer therapy within 21 days prior to first dose. Note: Luteinizing hormone-releasing hormone (LHRH) agonists or antagonists to maintain castrate levels of testosterone in patients with hormone-refractory prostate cancer is allowed. Oral contraceptives and estrogen/progestogen hormone replacement therapy are acceptable.
5. Radiation or surgery within 14 days prior to first dose, thoracic radiation within 28 days prior to first dose. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
6. Has known active central nervous (CNS) metastases and/or carcinomatous meningitis. Or has neurologic instability per clinical evaluation due to tumor involvement of the CNS. However, patients who have received prior radiotherapy for previous brain metastasis may be enrolled if they have discontinued steroids for at least 28 days prior to first treatment of study drug and be asymptomatic and clinically stable (without evidence of progression by CT or MRI for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have return to baseline).
7. Requirement for corticosteroid treatment (with the exception of megestrol and local use of steroid: i.e., topical corticosteroids, inhaled corticosteroids for reactive airway disease, ophthalmic, intraarticular, and intranasal steroids). Patients who received prior therapy with corticosteroids must have discontinued use of corticosteroid therapy 14 days prior to the first dose of APG-115; the patients who require replacement dose corticosteroids are allowed (e.g., if they have had endocrinopathy from ipilimumab). Subjects that are expected to require premedication with corticosteroid for PD-1 treatment will not be eligible for this study. Note: Patients who have received their last chemotherapy > 21 days ago, but are off prednisone for ≤ 14 days are eligible
8. Concurrent treatment with an investigational agent or device within 21 days prior to the first dose of therapy
9. Failure to recover adequately, as judged by the investigator, from prior surgical procedures. Patients with active wound healing, patients who have had major surgery within 28 days from 1st dose of study treatment, and patients who have had minor surgery within 14 days from 1st dose of study treatment
10. Unstable angina, myocardial infarction, or a coronary revascularization procedure within 180 days of study entry
11. Active rheumatoid arthritis (RA), active inflammatory bowel disease, chronic infections, or any other disease or condition associated with chronic inflammation
12. Active infection requiring systemic antibiotic/ antifungal medication and known clinically active viral infection such as hepatitis B or C, HIV infection, or active COVID-19.
13. Uncontrolled concurrent illness including, but not limited to: symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with the study requirements
14. Has an active autoimmune disease, or a documented history of autoimmune disease, or a syndrome, that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections are not excluded from the study. Subjects with hypothyroidism stable on hormone replacement are not excluded from the study.
15. Has received a live vaccine within 30 days prior to first dose. Note that killed vaccines, mRNA vaccines, and non-live attenuated vaccines (i.e., for the SARS-Cov-2 virus or COVID-19) are allowed for patients on study.
16. Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant.
17. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
18. Has previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb).
19. Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.
20. History of organ transplant requiring use of immunosuppressive medication.
21. A woman of childbearing potential (WOCBP) who has a positive urine or serum pregnancy test (within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
