This phase I trial studies the side effects and best dose of olaparib and onalespib when given together in treating patients with solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable) or ovarian, fallopian tube, primary peritoneal, or triple-negative breast cancer that has come back (recurrent). Olaparib and onalespib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Active, not recruiting
Phase 1
| Drug | Synonyms | Arms |
|---|---|---|
| Olaparib | AZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281 | Treatment (olaparib and onalespib) |
| Onalespib | AT 13387, AT-13387, AT13387 | Treatment (olaparib and onalespib) |
PRIMARY OBJECTIVE:
I. To establish the maximum tolerated dose (MTDs) of olaparib and onalespib (AT13387)
administered in combination in patients with advanced solid tumors.
SECONDARY OBJECTIVES:
I. To identify the dose-limiting toxicity (DLT) and other toxicities associated with olaparib
and AT13387 administered in combination as assessed by Common Terminology Criteria for
Adverse Events (CTCAE) version (v) 5.0.
II. To determine the recommended phase 2 doses (RP2D) of the combination of olaparib and
AT13387.
III. To determine the plasma pharmacokinetics of olaparib and AT13387. IV. To document
anti-tumor activity of the combination of olaparib and AT13387 as assessed by Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1 and progression free survival (PFS).
Although the clinical benefit of [this/these] drug(s) has not yet been established, the
intent of offering this treatment is to provide a possible therapeutic benefit, and thus the
patient will be carefully monitored for tumor response and symptom relief in addition to
safety and tolerability.
EXPLORATORY OBJECTIVES:
I. To test the hypothesis that there will be induction of BRCA1 and RAD51 foci after olaparib
alone and reduced formation of these foci after the combination of AT13387 and olaparib,
assessed immunohistochemically.
II. To assess downregulation of expression of HR pathway genes after the combination of
AT13387 and olaparib.
III. To assess whether there is induction of BRCA1 and RAD51 foci after olaparib alone
assessed immunohistochemically in the optional biopsy performed after olaparib alone compared
to the optional baseline biopsy prior to initiation of the study.
IV. To assess whether there is reduction of BRCA1 and RAD51 foci after the combination of
olaparib and AT13387 assessed immunohistochemically in the optional biopsy performed after
one of the combination olaparib and AT13387 doses (compared to the optional biopsy after
olaparib alone).
V. To assess whether there is induction of HSP70 (a known biomarker of HSP90 inhibition)
after the combination of olaparib and AT13387 assessed immunohistochemically in the optional
biopsy performed after one of the combination olaparib and AT13387 doses (compared to the
optional biopsy after olaparib alone).
VI. To assess whether there is downregulation of expression of HR pathway genes after the
combination of AT13387 and olaparib assessed by Nanostring in the optional biopsy performed
after one of the combination olaparib and AT13387 doses (compared to the optional biopsy
after olaparib alone).
VII. To assess whether there is induction of phosphorylation (phospho) H2AX after the
combination of AT13387 and olaparib assessed by immunohistochemistry in the optional biopsy
performed.
VIII. To assess whether there is downregulation of CCNE1 after the combination of AT13387 and
olaparib assessed by immunohistochemistry in the optional biopsy performed.
OUTLINE: This is a dose-escalation study.
Patients receive olaparib orally (PO) twice daily (BID) on days 1-7 (cycle 0). Beginning in
cycle 1, patients receive olaparib PO BID on days 1-28 and onalespib intravenously (IV) over
1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeat every 28 days in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and every 3 months
for up to 2 years.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Treatment (olaparib and onalespib) | Experimental | Patients receive olaparib PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients receive olaparib PO BID on days 1-28 and onalespib IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
|
Inclusion Criteria:
- For the dose escalation cohort, patients must have histologically or cytologically
confirmed malignancy that is metastatic or unresectable and for which standard
curative or palliative measures do not exist or are no longer effective
- For the dose escalation cohort, patients may have received any number of prior
therapies
- For the dose expansion cohort, participants must have histologically or cytologically
confirmed diagnosis of either:
- Ovarian, fallopian tube, or primary peritoneal cancer of high grade serous
histology which has recurred despite standard therapy; up to 3 prior lines in the
platinum resistant setting (i.e. up to 3 lines after patients have become
platinum resistant); patients may have received unlimited lines while platinum
sensitive
- Triple-negative breast cancer (TNBC) which has recurred despite standard therapy;
recurrent TNBC needs to have metastatic disease and patients with an in breast
recurrence are not eligible; up to 4 prior lines in the recurrent setting for
patients with triple-negative breast cancer are allowed
- For the dose expansion cohort, patients with ovarian, fallopian tube or primary
peritoneal cancer must have platinum resistant disease defined as progression within 6
months after last platinum regimen; platinum refractory disease is allowed
- For the dose expansion cohort, patients with triple-negative breast cancer may not be
BRCA1/2 germline mutation carriers
- Because no dosing or adverse event data are currently available on the use of olaparib
in combination with AT13387 in patients < 18 years of age, children are excluded from
this study, but will be eligible for future pediatric trials.
- There must be availability of a formalin-fixed, paraffin-embedded tumor specimen
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky > 60%)
- Life expectancy of greater than 12 weeks
- Leukocytes >= 3,000/mcL
- Hemoglobin >= 10 g/dL with no blood transfusion in the past 28 days
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional upper limit of normal
- Creatinine =< the institutional upper limit of normal OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- Corrected QT using Fridericia's formula (QTcF) =< 450 ms
- Any clinically significant electrolyte imbalance, particularly hypokalemia and
hypomagnesemia, should be corrected before treatment
- Pre-study evaluation must include an ophthalmologic exam by an ophthalmologist (not
optometrist) and should minimally include visual acuity testing, slit lamp
examination, and funduscopic examination; follow up eye-exams will only be performed
if subjects develop/report any visual impairment; visual impairment may include
peripheral flashes (photopsia), blurred or double vision, floaters, color distortion
and dimness, difficulties with light/dark accommodation, tunnel vision or other field
defects, halos, apparent movement of stationary objects, and complex disturbances;
follow up eye-exams will minimally include visual acuity testing, slit lamp
examination, and funduscopic examination; additional testing will be based on
symptoms, what is observed and ophthalmologist recommendations
- For the expansion cohort only: measurable disease by RECIST v1.1 with at least one
measurable target lesion
- The effects of olaparib in combination with AT13387on the developing human fetus are
unknown; for this reason and because olaparib and AT13387 are anti-neoplastic small
molecule inhibitors, which are agents that are potentially teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, for the duration of
study participation, and for 3 months after the last dose of study drugs; should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately; men
treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of study participation, and 4 months after
completion of olaparib and/or AT13387 administration
- Patients must be able to swallow tablets and have no significant impairment in
gastrointestinal absorption
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier
- All acute, clinically significant treatment-related toxicity from prior therapy,
except for alopecia, must have resolved to grade =< 1
- Patients who are receiving any other investigational agents
- Patients with known active or history of brain metastases should be excluded from this
clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to olaparib and AT13387 used in study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because olaparib and AT13387 are agents
with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with AT13387 or olaparib, breastfeeding should be discontinued
if the mother is treated with olaparib or AT13387
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
olaparib or AT13387; in addition, these patients are at increased risk of lethal
infections when treated with marrow-suppressive therapy; appropriate studies will be
undertaken in patients receiving combination antiretroviral therapy when indicated
- Known history of QT/corrected QT (QTc) prolongation or torsades de pointes (TdP);
patients who are currently receiving treatment with medication with a known risk to
prolong the QT interval or inducing torsades de pointes and the treatment cannot
either be discontinued or switched to a different medication prior to starting study
drugs
- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 or moderate inhibitors of CYP3A4 are ineligible; the study team
should check a frequently-updated medical reference for a list of drugs to avoid or
minimize use of; as part of the enrollment/informed consent procedures, the patient
will be counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the patient is considering a new
over-the-counter medicine or herbal product
- Participants with myelodysplastic syndrome/acute myeloid leukemia or with features
suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Maximum tolerated dose |
| Time Frame: | Up to 35 days |
| Safety Issue: | |
| Description: | Defined as the highest dose at which 0 of 3 or 1 of 6 or fewer patients experience a dose-limiting toxicity. Based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. |
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | National Cancer Institute (NCI) |
August 31, 2021
