A phase I study of niraparib and pimitespib in patients with solid tumor

JRCT ID: jRCT2031220179

Registered date:02/07/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: unresectable recurrent solid tumor
• Date of first enrollment: 01/09/2022
• Target sample size: 48
• Study type: Interventional

Intervention(s)

[Dose-escalation part]
Tolerability of combination therapy with niraparib and pimitespib in the dose-escalation part will be assessed, and the recommended dose (RD) in the dose-expansion part will be determined.
The doses of niraparib and pimitespib will start at dose level 1 and move to dose level 2, dose level 3 or dose level -1 according to the criteria.
Level -1 : niraparib 100 mg/day, pimitespib 80 mg/day
Level 1 : niraparib 200 mg/day, pimitespib 80 mg/day
Level 2 : niraparib 200 mg/day, pimitespib 120 mg/day
Level 3 : niraparib 200 mg/day, pimitespib 160 mg/day
Niraparib will be administered orally QD. Pimitespib will be administered orally in 5 consecutive days followed by 2 days off. One cycle is defined as 4 weeks.

[Dose-expansion part]
The RD determined on the results of the dose-escalation part will be administered.

Outcome(s)

• Primary Outcome: Incidence of DLTs in the dose-escalation part

Secondary Outcome

- Incidence of adverse events
- ORR : Objective response rate
- CA125 response rate
- PSA response rate
- PFS : Progression-free survival
- DoR : Duration of response
- TTF : Time to treatment failure
- DCR : Disease control rate
- OS : Overall survival
- Percent change from baseline in the sum of tumor diameterts

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1.Patients who have voluntarily provided written consent for participation in the study.
2.Patients aged 18 years or older at the time of providing informed consent.
3.Patients diagnosed with solid tumor who :
[Dose-escalation part]
i. Histologically or cytologically confirmed unresectable or recurrent solid tumor (any type of cancer, and any history of prior PARP inhibitor)
ii. Have a history of chemotherapy of 1 or more regimens (endocrine therapy is not counted in the number of regimens)
Note : Adjuvant chemotherapy is counted as one regimen if recurrence is observed during or within 6 months of the last administration of adjuvant chemotherapy.
[Dose-expansion part : Cohort A]
i.Histologically or cytologically confirmed unresectable or recurrent breast/ovarian/fallopian/peritoneal/prostate/pancreatic cancer
ii. Confirmed germline or somatic pathogenic BRCA variant (deleterious or suspected deleterious)
iii. Have received a PARP inhibitor (olaparib/niraparib/talazoparib/rucaparib), and progressed during or within 2 months of the last administration of prior PARP inhibitor. In patients who determined progression by the criteria other than RESICT version 1.1, the investigator need to discuss and obtain agreement from Clinical Trial Coordinating Committee.
iv. No intervening chemotherapy after the last administration of prior PARP inhibitor to the start of the protocol treatment.
v. Measurable disease according to RECIST version 1.1
[Dose-expansion part: Cohort B]
i. Histologically or cytologically confirmed unresectable or recurrent solid tumor excluding ovarian/fallopian/peritoneal cancer
ii. Meet one of the following
a. Breast cancer without germline pathogenic BRCA variant
b. Prostate cancer without pathogenic BRCA variant
c. Pancreatic cancer without germline pathogenic BRCA variant
d. Other solid tumor (any genetic alteration)
iii. Have a history of chemotherapy of 1 or more regimens (endocrine therapy is not counted in the number of regimens)
Note : Adjuvant chemotherapy is counted as one regimen if recurrence is observed during or within 6 months of the last administration of adjuvant chemotherapy.
iv. Have no history of prior PARP inhibitor
v. Measurable disease according to RECIST version 1.1

4.Patients with PS (ECOG) of 0 to 1
5.Life expectancy of at least 12 weeks
6.Patients who have adequate organ function and whose latest laboratory results within 7 days prior to enrollment meet all the following criteria.
Note: Results obtained within 14 days after administration of blood transfusion or granulocyte colony-stimulating factor (G-CSF) are excluded.
-ANC >= 1500 /mm3
-Platelet count >= 100,000/ mm3
-Hemoglobin >= 9.0 g/dL
-Calculated (with the Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min
-Total bilirubin <= 1.5XULN (patients with gilbert's syndrome if they have > 2.0 mg/dl will be allowed after agreement from Clinical Trial Coordinating Committee)
-AST, ALT<=100 IU/L
7.In female of childbearing potential, negative for pregnancy test within 7 days prior to enrollment.
8.In female of childbearing potential or female partner, patients who agree to contraception for the period from informed consent to at least 7 months after the last administration of the protocol treatment. In male and male partner, patients who agree to contraception and not to donating sperm for the period from the start of the protocol treatment to at least 4months after the last administration of the protocol treatment.
9.Female agree not to breastfeed for the period from informed consent to at least 1 month after the last administration of the protocol treatment.
10. Patients who are able to take medication orally.

Exclude criteria

1.Patients with a history of HSP90 inhibitor (for example Pimitespib, Ganetespib, Luminspib, Onalespib, Retaspimycin, Tanespimycin, Alvespimycin, BIIB021 etc.)
2.Patients with symptomatic brain metastases or meningeal dissemination
3.Patients with the following previous or current history
-Uncontrol ascites, pleural or pericardial effusion
-QT prolongation syndrome
-Interstitial pneumonia
-Psychosis or propensity for medication overuse
4.Patients who are pregnant or breastfeeding
5.Patients with history of other malignancies within 3 years prior to enrollment.
However, patients with history of carcinoma situ which are considered to be cured by local treatment, lesions equivalent to intramucosal carcinoma or non-metastatic prostate cancer requiring systemic treatment are excluded.
6.Pateints who require the following anticancer therapy
-Any prior therapy (including chemotherapy, molecular targeted therapy, antibody therapy, hormone therapy or immune therapy) within 14 days before the start of the protocol treatment. However, bisphosphonate or denosumab for bone lesion, LH-RH agonist or GnRH antagonist for prostate cancer are allowed.
-Radiation therapy or Radiopharmaceutical therapy within 28 days before the start of the protocol treatment. However, palliative radiation therapy within 14 days before the start of theprotocol treatment is allowed.
7. Patients who have the following infectious diseases
- HBsAg-positive
Note : Patients with HBV-DNA level < 20 IU/mL (1.3 logIU/mL) under taking entecavir are allowed.
-HBsAb-positive or HBcAb-positive
Note : Patients with HBV-DNA level < 20 IU/mL (1.3 logIU/mL) are allowed.
-HCVAb-positive
Note : Patients with HCV-RNA level below the detect limit are allowed.
-HIV
Note : Patients with positive for HIV screening test are allowed if the HIV confirmation test is negative.
8. Patients who have other active infectious diseases requiring treatment.
9.Patients who are receiving systemic steroids or immunosuppressive drug therapy at enrollment.
Note : It is allowed in the following cases.
- A dose <= 10 mg / day of prednisolone
- Temporary use for testing or prophylactic administration for allergic reactions, or for reduction of edema associated with radiotherapy
10. Patients who does not have recovered from any adverse events (AEs) of previous anticancer therapy.
Note : Hematological abnormality meet inclusion criteria 6, CTCAE grade 2 peripheral neuropathy, alopecia, hyperpigmentation, and the cases judged by the investigator to have no safety problems are allowed.
11. Patients with myocardial infarction, congestive heart failure (New York Heart Association class III or IV), unstable angina or arrhythmia requiring treatment within 6 months prior to enrollment.
12. Patients who have a history of major surgery (minimal surgery is excluded, for example lymph node biopsy, core biopsy or implantation of port etc.) within 4 weeks prior to enrollment.
13. Patients whose collected visual acuity <0.5 (in accordance with international visual acuity measurement standards).
14. Patients with other significant abnormalities.
15. Patients who are regarded as inappropriate for enrollment by investigators.

Related Information

• Primary Sponsor: Naito Yoichi
• Source(s) of Monetary Support: Takeda Pharmaceutical Co., Ltd.,Taiho Pharmaceutical Co., Ltd.