NCT03024437

Atezolizumab in Combination With Entinostat and Bevacizumab in Patients With Advanced Renal Cell Carcinoma

Terminated Phase 1, PHASE2 Results posted Last updated 20 March 2025

What this trial tests

Phase 1, PHASE2 trial testing Atezolizumab in Metastatic Cancer in 31 participants. Terminated before completion.

Timeline

29 June 2017

Primary endpoint
24 June 2024

24 June 2024

Quick facts

Lead sponsor	Roberto Pili
Phase	Phase 1, PHASE2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	non randomized
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	31
Start date	29 June 2017
Primary completion	24 June 2024
Estimated completion	24 June 2024
Sites	4 locations across United States

Drugs / interventions tested

• Atezolizumab (atezolizumab) — full drug profile →
• Bevacizumab (Bevacizumab-Bvzr) — full drug profile →
• Entinostat

Conditions studied

• Metastatic Cancer — all drugs for Metastatic Cancer →
• Renal Cancer — all drugs for Renal Cancer →

Sponsor

Roberto Pili

Who can join

18 and older, any sex, with Metastatic Cancer or Renal Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Phase I: Recommended Phase II Dose of Entinostat Primary · 21 days

Three dose levels of entinostat (1 mg, 3 mg and 5 mg) were tested according to the 3 + 3 standard design. The starting dose level of entinostat was 1 mg orally every 7 days. DLTs attributable to entinostat and/or bevacizumab and/or atezolizumab were evaluated during the first 21 days of the combination treatment. If a DLT occurs in 1 patient treated at the starting dose level, a minimum of 3 additional patients will be treated at this dose level. If DLTs occur in 2 or more of the first 6 patients, the study will be terminated. If a DLT occurs in 1 out of 6 patients, 3 additional patients will

Group	Value	95% CI
Phase I - Dose Escalation	5

Phase II: Percentage of Patients With Objective Response Primary · Up to 1 year

Percentage of patients who achieved a complete response or partial response to treatment as measured per RECIST 1.1. Complete response: Disappearance of all target lesions. Partial response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter.

Group	Value	95% CI
Phase II - Cohort A	62.5	35.4 – 84.8
Phase II - Cohort B	33.3	0.8 – 90.6

Phase I: Percentage of Patients With Objective Response Secondary · Up to 1 year

Percentage of patients who achieved a complete response or partial response to treatment as measured per RECIST 1.1. Complete response: Disappearance of all target lesions. Partial response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter.

Group	Value	95% CI
Phase I - Dose Level 1	50	11.8 – 88.2
Phase I - Dose Level 2	20	0.5 – 71.6
Phase I - Dose Level 3	83.3	35.9 – 99.6

Phase II: Median Progression-free Survival Secondary · Up to 4.5 years

Progression free survival was defined as the time from on treatment date to date of recurrence of any type or death from any cause. Patients who did not experience recurrence or death were censored at their last evaluation date. The Kaplan-Meier method was used to determine the median and 95% confidence interval.

Group	Value	95% CI
Phase II - Cohort A	13.7	8.7 – 21.3
Phase II - Cohort B	9.8	1.3 – NA

Phase II: Median Overall Survival Secondary · Up to 5.5 years

Overall survival was defined as the time from on treatment date to death due to any cause. Patients who remained alive were censored at their last known alive date. The Kaplan-Meier method was used to determine the median and 95% confidence interval.

Group	Value	95% CI
Phase II - Cohort A	51.6	21.8 – NA
Phase II - Cohort B	31.2	22.8 – NA

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 2.5 years for adverse events and up to 5.5 years for all-cause mortality.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase I - Dose Level 1

Serious: 3/6 (50%)

Deaths: 6/6

Phase I - Dose Level 2

Serious: 5/6 (83%)

Deaths: 5/6

Phase I - Dose Level 3

Serious: 6/6 (100%)

Deaths: 4/6

Phase II - Cohort A

Serious: 6/12 (50%)

Deaths: 4/12

Phase II - Cohort B

Serious: 0/1 (0%)

Deaths: 1/1

Serious adverse events (35 terms)

Reaction	System	Phase I - Dose Level 1	Phase I - Dose Level 2	Phase I - Dose Level 3	Phase II - Cohort A	Phase II - Cohort B
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—
Atrial flutter	Cardiac disorders	—	—	—	—	—
Sinus bradycardia	Cardiac disorders	—	—	—	—	—
Endocrine disorders - Other	Endocrine disorders	—	—	—	—	—
Hyperthyroidism	Endocrine disorders	—	—	—	—	—
Retinal detachment	Eye disorders	—	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—	—	—
Lower gastrointestinal hemorrhage	Gastrointestinal disorders	—	—	—	—	—
Oral hemorrhage	Gastrointestinal disorders	—	—	—	—	—
Rectal fistula	Gastrointestinal disorders	—	—	—	—	—
Non-cardiac chest pain	General disorders	—	—	—	—	—
Pain	General disorders	—	—	—	—	—
Allergic reaction	Immune system disorders	—	—	—	—	—
Lung infection	Infections and infestations	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—
Sinusitis	Infections and infestations	—	—	—	—	—
Spinal fracture	Injury, poisoning and procedural complications	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—
Blood bilirubin increased	Investigations	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—

Other adverse events (126 terms — click to expand)

Reaction	System	Phase I - Dose Level 1	Phase I - Dose Level 2	Phase I - Dose Level 3	Phase II - Cohort A	Phase II - Cohort B
Diarrhea	Gastrointestinal disorders	—	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—	—
Hypophosphatemia	Metabolism and nutrition disorders	—	—	—	—	—
Proteinuria	Renal and urinary disorders	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Creatinine increased	Investigations	—	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—	—	—
Hypothyroidism	Endocrine disorders	—	—	—	—	—
Gastroesophageal reflux disease	Gastrointestinal disorders	—	—	—	—	—
Fever	General disorders	—	—	—	—	—
Sinusitis	Infections and infestations	—	—	—	—	—
Upper respiratory infection	Infections and infestations	—	—	—	—	—
Alkaline phosphatase increased	Investigations	—	—	—	—	—
Lipase increased	Investigations	—	—	—	—	—
Anorexia	Metabolism and nutrition disorders	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Arthritis	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—	—	—	—
Skin and subcutaneous tissue disorders - Other	Skin and subcutaneous tissue disorders	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—
Anemia	Blood and lymphatic system disorders	—	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—	—
Hemorrhoids	Gastrointestinal disorders	—	—	—	—	—
Toothache	Gastrointestinal disorders	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—
Chills	General disorders	—	—	—	—	—
Edema limbs	General disorders	—	—	—	—	—
Localized edema	General disorders	—	—	—	—	—
Pain	General disorders	—	—	—	—	—
Skin infection	Infections and infestations	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—

Most-reported serious reactions: Pneumonitis, Atrial fibrillation, Atrial flutter, Sinus bradycardia, Endocrine disorders - Other, Hyperthyroidism, Retinal detachment, Colitis.

Data from ClinicalTrials.gov NCT03024437 adverse events section.

Sponsor's own description

This study will assess the immunomodulatory activity of entinostat in patients with advanced renal cell carcinoma receiving the PD-L1 inhibitor atezolizumab. The overall hypothesis is that entinostat will increase the immune response and anti-tumor effect induced by the PD-L1 inhibition by suppressing Treg function. We have chosen renal cell carcinoma that has been reported to respond to PD1/PD-L 1 inhibition. The schedule of entinostat is based on our previous experience with this agent. Based on our working hypothesis that low dose HDAC inhibitors will have a suppressive function on Tregs but not on T effector cells, the starting dose of entinostat will be 1 mg and will be escalated up to 5 mg rather than the 10 mg dose. The combination also with bevacizumab will provide an effective VEGF inhibition that may potentiate the immune response and anti-tumor effect induced by atezolizumab. The proposed dose and schedule for atezolizumab and bevacizumab has been shown to be well tolerated in prior Phase/I/II studies and is currently tested in a Phase III randomized study in patients with renal cell carcinoma with sunitinib as a control arm. The highest proposed dose level for entinostat (5 mg) represents 50% of the recommended Phase II dose for this compound as a single agent.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome.
   Alsaab HO, Sau S, Alzhrani R, Tatiparti K, et al · · 2017 · cited 1206× · PMID 28878676 · DOI 10.3389/fphar.2017.00561
2. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.
   Cheng Y, He C, Wang M, Ma X, et al · · 2019 · cited 760× · PMID 31871779 · DOI 10.1038/s41392-019-0095-0
3. Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer.
   Li K, Shi H, Zhang B, Ou X, et al · · 2021 · cited 687× · PMID 34620838 · DOI 10.1038/s41392-021-00670-9
4. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment.
   Yi M, Jiao D, Qin S, Chu Q, et al · · 2019 · cited 487× · PMID 30925919 · DOI 10.1186/s12943-019-0974-6
5. Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors.
   Weber R, Fleming V, Hu X, Nagibin V, et al · · 2018 · cited 422× · PMID 29942309 · DOI 10.3389/fimmu.2018.01310
6. Immune checkpoint therapy in liver cancer.
   Xu F, Jin T, Zhu Y, Dai C. · · 2018 · cited 299× · PMID 29843754 · DOI 10.1186/s13046-018-0777-4
7. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets.
   Yang J, Xu J, Wang W, Zhang B, et al · · 2023 · cited 251× · PMID 37217462 · DOI 10.1038/s41392-023-01480-x
8. Epigenetic modulation of antitumor immunity for improved cancer immunotherapy.
   Dai E, Zhu Z, Wahed S, Qu Z, et al · · 2021 · cited 224× · PMID 34930302 · DOI 10.1186/s12943-021-01464-x