Clinical trial NCT04055649: ONC201 Plus Weekly Paclitaxel in Patients With Platinum Refractory or Resistant Ovarian Cancer
Official title: Phase II Study of ONC201 Plus Weekly Paclitaxel in Patients With Platinum-Resistant Refractory or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Malignant Ovarian Epithelial Tumor
Platinum-Resistant Fallopian Tube Carcinoma
Platinum-Resistant Ovarian Carcinoma
Platinum-Resistant Primary Peritoneal Carcinoma
Recurrent Fallopian Tube Carcinoma
Recurrent Ovarian Carcinoma
Recurrent Primary Peritoneal Carcinoma
Refractory Fallopian Tube Carcinoma
Refractory Ovarian Carcinoma
Refractory Primary Peritoneal Carcinoma
Lead sponsor: Barbara Ann Karmanos Cancer Institute
Sponsor class: OTHER
First posted: 2019-08-14
Enrollment: 62
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II trial studies the side effects of ONC201 and paclitaxel and how well they work in treating patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer that has come back (recurrent), or that does not respond to treatment (refractory). ONC201 is the first in its class of drugs that antagonize some specific cell receptors on cancer cells, leading to their destruction. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ONC201 and paclitaxel may work better in treating patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer compared to paclitaxel alone.

Detailed description: PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of the combination of Akt/ERK inhibitor ONC 201 (ONC201) and paclitaxel in patients with platinum refractory or resistant epithelial ovarian, fallopian tube or primary peritoneal cancer. (Part 1) II. To evaluate the objective response rate (ORR) of ONC201 in combination with paclitaxel in patients with platinum refractory or resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. (Part 2) III. To evaluate progression free survival (PFS) of ONC201 in combination with weekly paclitaxel in patients with platinum refractory or resistant epithelial ovarian, fallopian tube or primary peritoneal cancer. (Part 2)

SECONDARY OBJECTIVES:

I. To evaluate the durability/duration of response (DOR) of ONC201 in combination with paclitaxel.

II. To evaluate the safety and patient reported tolerability of ONC201 in combination with paclitaxel. (Part 2) III. To evaluate the disease control rate (DCR) of ONC201 in combination with paclitaxel.

IV. To evaluate the cancer antigen-125 (CA-125) and/or human epididymis factor 4 (HE-4) response of ONC201 in combination with paclitaxel in those patients with one or both of these tumor markers upregulated.

V. To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of ONC201 in combination with paclitaxel.

VI. To obtain preliminary estimates of overall survival (OS) of ONC201 in combination with weekly paclitaxel.

EXPLORATORY OBJECTIVES:

I. To evaluate the immune response (specifically natural killer \[NK\] cell and cytokine profile) of ONC201 in combination with paclitaxel in patients with platinum refractory or resistant epithelial ovarian, fallopian tube or primary peritoneal cancer.

OUTLINE:

Patients receive ONC201 orally (PO) on days 1, 8, and 15, and paclitaxel intravenously (IV) over 1 hour on days 2, 9, and 16. Cycles repeat every 28 days in the absence disease progression or unacceptable toxicity. If paclitaxel must be stopped for any reason, patients may continue on ONC201 alone.

After completion of study treatment, patients are followed up for 1 year.

Eligibility criteria: Inclusion Criteria:

* Histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer.
* Progressed within 6 months of completing at least 1 cycle of last platinum containing regimen. Patients with refractory disease (progression during platinum-containing therapy) are eligible. This includes both adjuvant therapy and in the recurrent setting.
* No more than 4 prior treatment regimens defined as investigational, chemotherapy, hormonal, biologic, or targeted therapy in the platinum resistant setting and total of 7 prior regimens in all settings will be allowed. Prior maintenance therapy with biologic or targeted agent does NOT count as a treatment regimen (e.g. Maintenance bevacizumab, Parpi, or immunotherapy).
* At least one measurable lesion according to RECIST v1.1.
* For the eight patients enrolled for PK/PD. Availability of tissue from carcinoma. For most patients this will be archival tissue. If there is no archival tissue available, biopsy of lesion MUST be performed prior to initiation of therapy. Lesions must be available for biopsy as well in these patients.
* Any prior palliative radiation therapy must be completed at least 7 days prior to start of study treatment and patients must have recovered from any acute adverse effects prior to start of study treatment.
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1.
* Female patients who are not of childbearing potential and fertile female patients of childbearing potential who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 3 days prior to start of study treatment.
* Patients must have adequate (at baseline):

  1. Bone marrow function: Absolute neutrophil count (ANC) ≥1,500/µL. Platelets

     ≥100,000/µL and hemoglobin \> 8.0 gm/dL, transfusion allowed up to 1 week prior to maintain Hgb \>8.
  2. Renal function: Calculated creatinine clearance (CrCl) ≥35 mL/min/1.73 mm2
  3. Hepatic function: Bilirubin less than or equal to 1.5 x ULN; alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase (ALT) less than or equal to 3 x ULN. AP, AST and ALT less than or equal to 5 x ULN is acceptable if patient has known hepatic metastasis

Exclusion Criteria:

* Use of a study drug (approved or investigational drug therapy) ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of study treatment. For study drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the study drug and administration of current study treatment is required.
* Major surgical procedures ≤21 days of beginning study treatment, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement, ureteral stent placement, percutaneous nephrostomy tube placement.
* No other (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy \[except for palliative local radiotherapy\]), biological therapy or other novel agent is to be permitted while the patient is receiving study medications
* Grade \>1 toxicity from prior therapy (except alopecia or anorexia or above hematologic criteria) unless controlled by medications.
* Inability to swallow oral medication. Note: Patient may not have a percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN) on this trial.
* Known malignant central nervous system disease other than neurologically stable, treated brain metastases - defined as metastasis having no evidence of progression after treatment for at least 4 weeks (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrollment.
* Patient has had prescription or non-prescription drugs or other products (i.e. grapefruit juice) known to be moderate to strong inhibitors or inducers of CYP3A4, which cannot be discontinued 1 week prior to Day 1 of dosing and withheld throughout the study until 1 weeks after the last dose of study drug.
* Any known hypersensitivity or contraindication to the components of study treatment
* Pregnant or lactating
* Serious active infection at the time of enrollment, or another serious underlying medical condition at discretion of the enrolling physician that would impair the ability of the patient to receive study treatment. HIV or other immunodeficiency disease that is well controlled and that does not impact baseline lab values (i.e. outside of above noted parameters for inclusion) are NOT considered exclusion criteria.
* Presence of other active cancers other than ovarian cancer except those that do not require active therapy (i.e. on surveillance) and known non-invasive cancers and in situ cancers (e.g. non-melanoma skin cancers).
* Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

Primary outcomes:
measure: Incidence of treatment related adverse events (AEs) (Part 1)
timeFrame: Up to 28 days
measure: Incidence of dose limiting toxicities (DLT's) (Part 1)
timeFrame: Up to 28 days
measure: Objective response rate (ORR) (Part 2)
timeFrame: Up to 1 year
measure: Progression free survival (PFS) (Part 2)
timeFrame: From study treatment initiation to objective tumor progression or death, assessed up to 1 year
Secondary outcomes:
measure: Duration of response (DOR)
timeFrame: From first documented tumor response until the date of documented progression or death from any cause, assessed up to 1 year
measure: Incidence of treatment related AEs
timeFrame: Up to 1 year
measure: Incidence of patient reported symptoms
timeFrame: Up to 1 year
measure: Disease clinical response (DCR)
timeFrame: At 6 months
measure: CA-125 response rate
timeFrame: Up to 1 year
measure: HE-4 response rate
timeFrame: Up to 1 year
measure: Plasma concentrations of ONC201
timeFrame: Up to 1 year
measure: Pharmacodynamic studies
timeFrame: Up to 1 year
measure: Overall survival
timeFrame: From study treatment initiation to death, assessed up to 1 year
Other outcomes:
measure: NK cell evaluation
timeFrame: Up to 1 year
measure: Cytokine profile
timeFrame: Up to 1 year
Locations:
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Flint
country: United States
facility: Karmanos Cancer Institute at McLaren Flint
state: Michigan
Study officials:
affiliation: Barbara Ann Karmanos Institute
name: Ira Winer, M.D.
role: PRINCIPAL_INVESTIGATOR
References: