TH-125: A Randomized Phase 2 Study of Nivolumab Plus Ramucirumab in Patients With Recurrent, Advanced, Metastatic Non-Small Cell Lung Carcinoma

Nivolumab Plus Ramucirumab in Patients With Recurrent, Advanced, Metastatic NSCLC



Sponsors


Source

Fox Chase Cancer Center

Oversight Info

Has Dmc

Yes

Is Fda Regulated Drug

Yes

Is Fda Regulated Device

No


Brief Summary

Cohort A in this study will enroll Immuno-oncology (IO) naïve patients who have progressed on
previous chemotherapy or targeted therapies. The subjects will be randomized 2:1(combination:
nivolumab monotherapy), with primary endpoint of 6-months PFS.

Cohort B will enroll patients with prior IO therapy (alone or in combination with
chemotherapy or in combination with other IO agents), into a non-randomized combination
trial, with primary endpoint of disease control rate.

Overall Status

Not yet recruiting

Start Date

2018-12-01

Completion Date

2023-04-01

Primary Completion Date

2020-04-01

Phase

Phase 2

Study Type

Interventional

Primary Outcome

Measure

Time Frame

Number of patients with progression free survival (PFS) at 6 months in IO naive patients.treated with nivolumab and ramucirumab combination therapy vs the nivolumab monotherapy
6 months
Disease control rate (DCR) in IO experienced patients.treated with nivolumab and ramucirumab combination therapy
12 months

Secondary Outcome

Measure

Time Frame

Overall Response Rate (ORR) in IO naive patients treated with nivolumab and ramucirumab combination therapy
12 months
Overall Response Rate in IO naive patients treated with nivolumab monotherapy
12 months
Number of patients with treatment related toxicities in IO naive patients treated with nivolumab and ramucirumab combination therapy
12 months
Number of patients with treatment related toxicities in IO naive patients treated with nivolumab monotherapy
12 months
Overall survival in IO naive patients treated with nivolumab and ramucirumab combination.
60 months
Overall survival in IO naive patients treated with nivolumab monotherapy
60 months
Number of patients with PFS at 6 months in IO experienced patients treated with nivolumab and ramucirumab combination therapy .
6 months
ORR in IO experienced patients treated with nivolumab and ramucirumab combination therapy .
12 months
Number of patients with treatment related toxicities in IO experienced patients treated with nivolumab and ramucirumab combination therapy .
12 months
Overall survival in IO experienced patients treated with nivolumab and ramucirumab combination therapy .
60 months

Enrollment

117

Condition


Intervention

Intervention Type

Drug

Intervention Name


Description

78 patients diagnosed with non-small cell lung cancer, regardless of histology, immunotherapy-naive, after progression through one line of treatment with an appropriate chemotherapy regimen (platinum doublet, or after appropriate targeted therapies). Normal organ function, Performance Status (PS)- 0-1, no active autoimmune disease, no hemoptysis or cavitary tumor. Core biopsy specimen must be available.
39 patients diagnosed with non-small cell lung cancer, regardless of histology, immunotherapy-exposed, after progression through one line of treatment with an appropriate regimen (immunotherapy alone, or immunotherapy plus chemotherapy). Normal organ function, PS 0-1, no active autoimmune disease, no hemoptysis or cavitary tumor. Core biopsy specimen must be available.

Arm Group Label

Immuno-Oncology naive patients

Immuno-Oncology experienced patients



Intervention Type

Drug

Intervention Name


Description

78 patients diagnosed with non-small cell lung cancer, regardless of histology, immunotherapy-naive, after progression through one line of treatment with an appropriate chemotherapy regimen (platinum doublet, or after appropriate targeted therapies). Normal organ function, PS 0-1, no active autoimmune disease, no hemoptysis or cavitary tumor. Core biopsy specimen must be available.

Arm Group Label

Immuno-Oncology naive patients



Eligibility

Criteria

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed, refractory or recurrent,
advanced non-small cell lung carcinoma regardless of histology.

2. Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension in accordance with RECIST criteria v.
1.1 as described in detail in section 11.0

3. Patients must have completed one line of prior therapy in both cohorts. For
participation in the Cohort A, they must have completed at least 4 cycles of platinum
doublet therapy. For participation in Cohort B, they must have received PD-1, PD-L1
and/or CTLA-4 immunotherapy, alone or in combination with chemotherapy or in
combination with other IO agents. Treatment on this protocol may begin as long as the
patient has recovered from toxicities of prior therapy at the discretion of the
treating physician. A washout period of at least 2 weeks is required prior to starting
on this trial.

4. Patients with molecular targets (EGFR, ALK, ROS1) who have progressed on targeted
agents and are not eligible for other treatments or trials specific for this
population are allowed.

5. Age > 18 years.

6. ECOG performance status 0 or 1

7. Patients must have normal organ and marrow function as defined below. Patients should
be able to maintain ANC levels without the need for G-CSF transfusion. If blood
transfusion is performed for achieving hemoglobin levels, the levels should stay at ≥
9.0 mg/ml for at least a week after transfusion.

Absolute neutrophil count > 1,500/mcL Hemoglobin ≥ 9.0 mg/ml Platelets > 100,000/mcL
Total bilirubin ≤1.5 X institutional upper limit of normal (ULN) AST/ALT (SGOT/SGPT) <
3 times institutional normal limits, or up to 5 times institutional normal limits if
the patient has liver metastases Creatinine OR Creatinine clearance ≤1.5 X ULN, OR >
40 Ml/min/1.73 m2 for patients with creatinine levels above institutional normal as
per Cockcroft-Gault formula International Normalized Ratio (INR) or Prothrombin Time
(PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT
is within therapeutic range of intended use of anticoagulants Activated Partial
Thromboplastin Time (aPTT) <1.5 X ULN unless subject is receiving anticoagulant
therapy as long as PT or PTT is within therapeutic range of intended use of
anticoagulants

8. Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14
days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving
warfarin, the patient must have an INR ≤3.0. For heparin and LMWH there should be no
active bleeding (that is, no bleeding within 14 days prior to first dose of protocol
therapy) or pathological condition present that carries a high risk of bleeding (for
example, tumor involving major vessels or known varices).

9. Ability to understand and willingness to sign a written informed consent and HIPAA
consent document

10. A core tumor biopsy obtained after progression on the last treatment must be available
at study entry for the study. The biopsy sample must not be more than 90 days old at
the time of registration and the sample must be adequate for analyses. If the sample
is not adequate patient must agree to provide a fresh biopsy specimen before the start
of treatment. Any available archival tissue will also be collected.

11. The patient's urinary protein must be ≤1+ on dipstick or routine urinalysis (UA; if
urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must
demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol).

12. Female subject of childbearing potential should have a negative serum pregnancy within
72 hours prior to receiving the first dose of study medication.

13. Female subjects of childbearing potential and male subjects must be willing to use an
effective method of contraception - Contraception, for the course of the study through
150 days after the last dose of study medication.

14. Male patients who have women of child bearing potential (WOCBP) partners must agree to
use effective method of contraception - Contraception, for the course of the study
through 210 days after the last dose of study medication.

15. Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.

Exclusion Criteria:

1. Patients who have not recovered from their most recent chemotherapy or radiotherapy
prior to entering the study at the discretion of investigators. Patients may not be
currently receiving any other investigational agents or immunomodulatory agents (e.g.
ipilimumab). Patients treated with prior PD-1 or PD-L1 directed therapies are
ineligible Cohort A.

2. Prior ramucirumab treatment

3. The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first
dose of protocol therapy.

4. The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or
any other significant thromboembolism (venous port or catheter thrombosis or
superficial venous thrombosis are not considered "significant") during the 3 months
prior to first dose of protocol therapy.

5. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a
history of hepatic encephalopathy or clinically meaningful ascites resulting from
cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis
requiring diuretics or paracentesis.

6. The patient has experienced any arterial thromboembolic events, including but not
limited to myocardial infarction, transient ischemic attack, cerebrovascular accident,
or unstable angina, within 6 months prior to first dose of protocol therapy.

7. The patient has uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or
> 100 mmHg diastolic for >4 weeks) despite standard medical management.

8. The patient with history of hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon)
within 2 months prior to first dose of protocol therapy or with radiographic evidence
of intra-tumor cavitation or has radiologically documented evidence of major blood
vessel invasion or encasement by cancer.

9. The patient has a serious or non-healing wound, ulcer, or bone fracture (as per
physician's discretion) within 28 days prior to first dose of protocol therapy.

10. The patient has a prior history of GI perforation/fistula (within 6 months of first
dose of protocol therapy) or risk factors for perforation.

11. The patient has undergone major surgery within 28 days prior to first dose of protocol
therapy, or minor surgery/subcutaneous venous access device placement within 7 days
prior to first dose of protocol therapy. The patient has elective or planned major
surgery to be performed during the course of the clinical trial.

12. The patient is receiving chronic antiplatelet therapy other than aspirin, including
nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and
others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use
(maximum dose 325 mg/day) is permitted. Occasional use of NSAIDS is allowed
(occasional use would constitute daily use for less than a week; treating physician
discretion is permitted to differentiate between occasional Vs chronic use).

13. Patients who have not recovered from adverse events due to agents administered earlier
except neuropathy and alopecia. Physician's discretion is allowed to decide which
unresolved adverse events from previous therapy (for NSCLC) prohibit patient
participation in this study.

14. Patients with active autoimmune disease that has required systemic treatment in the
past 1 year (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Hormone replacement therapy (eg. thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment.

15. Patients requiring more than 10mg prednisolone (or its equivalent) per day are
excluded.

16. Patients with untreated symptomatic brain metastases are excluded. Patients with
treated brain metastases will be allowed if brain imaging obtained within 28 days of
trial enrollment reveals stable disease. Patients with small (<5mm) asymptomatic brain
metastasis are allowed to enroll.

17. Patients with interstitial lung disease or active, noninfectious pneumonitis. Patients
with active tuberculosis infection are excluded.

18. Patient who have received a live vaccine within 30 days prior to Cycle1 Day 1.

19. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia (significant), cirrhosis, or psychiatric illness/social situations that
would limit compliance with study requirements.

20. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS)

21. Known history of chronic hepatitis B virus infection or chronic hepatitis C virus
indicating chronic infection that is not cured.

22. Subjects with previous malignancies (except non-melanoma skin cancers, and in situ
cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma,
or breast) are excluded unless a complete remission was achieved at least 2 years
prior to study entry and no additional therapy is required or anticipated to be
required during the study period.

23. Pregnant or breast-feeding.

Gender

All

Minimum Age

18 Years

Maximum Age

N/A

Healthy Volunteers

No


Overall Official

Last Name

Role

Affiliation

Hossein Borghaei, DO
Principal Investigator
Fox Chase Cancer Center

Overall Contact

Last Name

Hossein Borghaei, DO

Phone

215-214-1515

Email



Location

Facility

Status

Contact

Fox Chase Cancer Center
Philadelphia Pennsylvania 19111 United States
Not yet recruiting
Last Name: Hossein Borghaei, MD

Location Countries

Country

United States


Verification Date

2018-07-01

Lastchanged Date

N/A

Firstreceived Date

N/A

Responsible Party

Responsible Party Type

Sponsor


Keywords


Has Expanded Access

No

Condition Browse


Secondary Id

TH-125

Number Of Arms

2

Intervention Browse

Mesh Term

Nivolumab

Ramucirumab

Antibodies, Monoclonal



Arm Group

Arm Group Label

Immuno-Oncology naive patients

Arm Group Type

Experimental


Arm Group Label

Immuno-Oncology experienced patients

Arm Group Type

Experimental



Firstreceived Results Date

N/A

Firstreceived Results Disposition Date

N/A

Study Design Info

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary Purpose

Treatment

Masking

None (Open Label)


Study First Submitted

May 4, 2018

Study First Submitted Qc

May 4, 2018

Study First Posted

May 16, 2018

Last Update Submitted

July 31, 2018

Last Update Submitted Qc

July 31, 2018

Last Update Posted

August 1, 2018


ClinicalTrials.gov processed this data on August 01, 2018

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



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