A Phase I/Ib, Open-label, Multi-center Study of DFF332 as a Single Agent and in Combination With Everolimus or IO Agents in Patients With Advanced/Relapsed ccRCC and Other Malignancies With HIF2alpha Stabilizing Mutations

JRCT ID: jRCT2031210239

Registered date:13/08/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Carcinoma, Renal Cell
• Date of first enrollment: 12/04/2022
• Target sample size: 180
• Countries of recruitment: Belgium,Japan,Czechia,Japan,France,Japan,Italy,Japan,Singapore,Japan,Spain,Japan,Switzerland,Japan,Republic of China,Japan,United States of America,Japan,Taiwan,Japan
• Study type: Interventional

Intervention(s)

DFF dose escalation part
Arm 1: DFF332 single agent
Arm 2: DFF332+Everolimus
Arm 3: DFF332+Spartalizumab+NIR178

DFF332 dose expansion part
Arm 1a: DFF332 single agent for ccRCC patients (>=18 years old)
Arm 1b: DFF332 single agent for malignancies with HIF stabilizing mutations (>=12 years old)
Arm 2a: DFF332+Everolimus for ccRCC (>=18 years old)
Arm 3a: DFF332+Spartalizumab+NIR178 for ccRCC (>=18 years old)

Outcome(s)

Primary Outcome

- Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including changes in laboratory parameters, vital signs and electrocardiograms (ECGs)
- Tolerability: Dose interruptions, reductions and dose intensity for both dose escalation and expansion
- Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 days) for DFF332 as a single agent and in combinations

Key inclusion & exclusion criteria

• Age minimum: >= 12age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

For dose escalation and expansion arms on SA and combos, with the exception of Arm1B:
1. Male and female >= 18 years of age
2. Histologically confirmed and documented clear cell renal cell carcinoma (ccRCC). Disease must be measureable as determined by RECIST v1.1.
3. Patient with unresectable, locally advanced or metastatic ccRCC with documented disease progression following therapy with PD-1/L1 checkpoint inhibitor and a VEGF targeted therapy as monotherapy or in combination.
Escalation: No restriction on the number of prior treatments
Expansion: Up to 3 prior lines of treatment for advanced/metastatic disease
4. ECOG performance status =<1

For basket arm (Arm 1B):
1. Male and female of age >= 12 years of age.
2. Histologically confirmed and documented malignancies in the context of the following cancer predisposing syndromes/disorders or harboring somatic mutations on one of these genes:
- Malignancies with VHL mutations (e.g. Von Hippel-Lindau disease)
- Malignancies with FH mutations (e.g. Hereditary leiomyomatosis and renal cell carcinoma)
- Malignancies with mutations in SDHD, SDHAF2, SDHC, SDHB, SDHA (e.g. Hereditary paraganglioma and pheochromocytoma syndrome)
- Malignancies with EPAS1/HIF2A mutations
- Malignancies with ELOC/TCEB1 mutations
3. Patients must have either metastatic disease or locally advanced disease that is unresectable or that patients be unfit for resection or other treatment modalities. Patients must have received prior standard therapy appropriate for their tumor type and stage of disease, and have no available therapies of proven clinical benefit; or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.
4. For patients age >= 16 years: ECOG performance status =< 1
For patients age >= 12 and < 16 years: Lansky performance status >= 70

Exclude criteria

1. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but limited to surgery, radiation and/or corticosteroids. Patients with treated symptomatic brain metastases should be neurologically stable for 4 weeks post-treatment prior to study entry and at doses =< 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
2. History of seizure disorder and/or extrapyramidal symptoms.
3. Known additional malignancy that is progressing or requires active treatment within the past 3 year(s). Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or other tumors that will not affect life expectancy.
4. Patients having out of range lab values during screening and before the first dose of study treatment. Out of range lab values are defined as:
- Absolute neutrophil count (ANC) <1.0 x 10e9/L
- Platelets <75 x 10e9/L
- Hemoglobin (Hgb) < 10g/dL
- Serum creatinine > 1.5 x ULN or creatinine clearance < 60mL/min using Cockcroft-Gault formula
- Total bilirubin > 1.5 x ULN , except for patients with Gilbert syndrome > 3.0 x ULN or direct bilirubin > 1.5 x ULN
- Aspartate aminotransferase (AST) > 3 x ULN
- Alanine aminotransferase (ALT) > 3 x ULN
- Serum electrolytes >= grade 2 despite adequate supplementation.
5. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
- =< 4 weeks for radiation therapy or limited field radiation for palliation within =< 2 weeks prior to the first dose of study treatment.
- =< 4 weeks or =< 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
- =< 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosourea and mitomycin C.
- =< 4 weeks for immuno-oncologic therapy, such as CTLA-4, PD-1, or PD-L1 antagonists.
6. Patients who have undergone major surgery =< 4 weeks prior to first dose of study treatment or who have not recovered for the surgical procedure.
7. Patient previously treated with a HIF2alfa inhibitor.

Related Information

• Primary Sponsor: Yonemura Masataka
• Secondary ID(s): NCT04895748