Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer
Prasanth Ganesan . Sarina Piha-Paul . Aung Naing . Gerald Falchook . Jennifer Wheler . Filip Janku . Ralph Zinner . Shell Laday . Merrill Kies · Apostolia M. Tsimberidou
Received: 14 June 2013 / Accepted: 13 August 2013 C Springer Science+Business Media New York 2013
Summary Background Lenalidomide, an immunomodulato- ry and anti-angiogenic drug, and temsirolimus, an mTOR inhibitor, have synergistic anti-cancer effects in preclinical models. We conducted a phase I study of the combination in patients with advanced cancers. Patients and methods A “3+ 3” study design was used. During the escalation phase, lenalidomide (orally, days 1-21) and temsirolimus (intrave- nously, once a week) were given at the following respective doses: level 1 (10 mg, 15 mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle=28 days). The maximum tolerated dose, dose-limiting toxicity, and re- sponse were assessed. Results Forty-three patients were treat- ed (median age: 58 years (range, 21-80); male/female: 26/17). The most common diagnoses were colorectal cancer (N=5), sarcoma (N=5), neuroendocrine carcinoma (N=4) and ade- noid cystic carcinoma (N=4). Overall, 121 cycles (median: 2) were administered. No dose-limiting toxicities were observed. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3-4 treatment-related hematologic toxicities (all reversible) were seen in 19 (72 %) patients and included neutropenia (N=12), thrombocytopenia (N=6), and infection (N=1). Grade 3 hyperglycemia and Grade 3 hypertriglyceridemia were noted in 21 % and 20 % of patients, respectively. Of 43 patients, 30 (70 %) received prophylactic
This research was supported in part by a research grant from Celgene to Dr. Tsimberidou.
P. Ganesan . S. Piha-Paul . A. Naing . G. Falchook . J. Wheler . F. Janku . R. Zinner . S. Laday . A. M. Tsimberidou Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030, USA e-mail: atsimber@mdanderson.org
M. Kies
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Unit 432, 1515 Holcombe Boulevard, Houston, TX 77030, USA
anticoagulation. There were no thrombotic events. Response was evaluable in 40 patients: one (2.5 %) patient had a partial response and 19 (48 %) had stable disease (SD), with SD ≥ 6 months in 6 (15 %) patients. Tumor types with SD ≥ 6 months were soft tissue sarcoma (2/5; 40 %), adenoid cystic carcinoma (1/4; 25 %), parotid adenocarcinoma (1/2; 50 %), adrenocortical carcinoma (1/3; 33 %), and neuroendocrine carcinoma (1/4; 25 %). The median progression-free survival duration was 2.2 months (95 % CI, 1.5-2.9), and the median overall survival duration was 7.8 months (95 % CI, 5.1-10.6). Conclusions Lenalidomide and temsirolimus combination therapy was well tolerated and associated with clinical benefit in patients with soft tissue sarcoma, adenoid cystic carcinoma, neuroendocrine carcinoma, parotid carcinoma, and adrenocor- tical carcinoma.
Keywords Lenalidomide . Temsirolimus . Phase I trial . Advanced cancer
Introduction
Lenalidomide is an immunomodulatory drug with anti- angiogenic properties that is currently approved for use in the treatment of multiple myeloma (MM) and 5q-deleted myelodysplastic syndrome [1-3]. Recent studies have dem- onstrated that lenalidomide has activity in a variety of solid tumors, although its efficacy as a single agent is modest [4]. A few studies have indicated that lenalidomide can be safely combined with cytotoxic chemotherapy, with possible syner- gistic effects [5, 6]. Therefore, the activity of lenalidomide against solid tumors could be enhanced by combining it with other anti-cancer agents.
Temsirolimus is an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1). It exerts its antitumor activity by inhibiting the PI3K/AKT/mTOR pathway, which
is involved in protein synthesis, cellular proliferation, and tumor angiogenesis [7, 8]. Temsirolimus is currently approved for the treatment of renal cell carcinoma.
In MM cell lines, the combination of the mTOR inhibitor rapamycin with lenalidomide was shown to be strongly synergistic, overcoming drug resistance when tested against MM cell lines resistant to conven- tional chemotherapy [9]. This combination could over- come the growth advantage conferred on MM cells by interleukin-6, insulin-like growth factor-1, or adherence to bone marrow stromal cells. It also induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase and the phos- phatidylinositol 3’-kinase/Akt pathways were targeted by these drugs individually and in combination, suggesting the molec- ular mechanism by which they interfere with MM growth and survival [9].
These previously published preclinical data [9] prompted the design and conduction of clinical trials with the combina- tion of temsirolimus and lenalidomide in relapsed multiple myeloma [10] or relapsed/refractory lymphoma [11]. This drug combination could yield responses in patients with lymphoma [11].
We designed a phase I trial to evaluate the combination of lenalidomide and temsirolimus in patients with advanced cancer. The primary objective was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of lenalidomide combined with temsirolimus. The secondary objective was to assess the antitumor efficacy of this combination.
Patients and methods
Eligibility criteria
Patients with histologically confirmed advanced or metastatic cancer that was refractory to standard therapy, had recurred after standard therapy, or for which there was no standard therapy available were eligible for the protocol. Participants had to have completed their previous anti-cancer therapy (cytotoxic chemotherapy, major surgery, or radiation therapy) at least 3 weeks prior to study entry (or ≥5 half-lives prior, if they had received targeted or biologic therapy). Participants were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and adequate renal (creatinine clearance ≥ 50 ml/min by Cockcroft-Gault formu- la), hepatic (total bilirubin < 2.0 mg/dL or alanine aminotrans- ferase ≤ 5 × upper normal reference value), and bone marrow (absolute neutrophil count ≥ 1,000 cells/uL and platelet count ≥ 100,000 cells/uL) function. Female patients of childbearing potential were eligible if they had a nega- tive urine or human chorionic gonadotropin serum test
and agreed to use effective contraception throughout study participation.
Patients were ineligible if they were pregnant or breast feeding or had any of the following: serious uncontrolled medical illness, psychiatric illness that limited their capacity to sign the consent documents, uncontrolled hypertension (systolic blood pressure >140 mmHg and diastolic blood pressure >90 mmHg on medication), history of deep vein thrombosis or pulmonary embolism, or significant cardiovascular dis- ease (history of myocardial infarction or history of cerebrovascular accident or unstable angina pectoris within the past 6 months).
All patients had to sign informed consent forms fully disclosing the investigational nature of the trial prior to enrollment. The protocol was approved by The Univer- sity of Texas MD Anderson Cancer Center Institutional Review Board.
Tumor molecular profiling (EGFR, GNAQ, PIK3CA, PTEN, TP53, KIT, KRAS, NRAS, and BRAF) was performed as previously described [12].
The temsirolimus and lenalidomide arm was one of four arms of an investigator-initiated clinical trial (www. clinicaltrials.gov, NCT01183663). The other arms were lenalidomide in combination with bevacizumab; sorafenib; and 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX).
Treatment plan
Lenalidomide was given orally on days 1-21 and temsirolimus was given intravenously on days 1, 8, 15, and 22 of a 28- day cycle. All treatment was given on an outpatient basis. During the escalation phase of the study, patients were treated with lenalidomide at 10 or 20 mg and with temsirolimus at 15, 20, or 25 mg (Table 1). Temsirolimus was administered intra- venously over 30 minutes after premedication with famotidine and diphenhydramine. New dose cohorts were initiated after a 30-day post-treatment observation period following enrollment of the last patient in each cohort. Prophylactic anticoagulation was strongly recommended but was not mandatory and was given at the discretion of the treating physician. Patients re- ceived full supportive care, including transfusions of blood and blood products, antibiotics, and antiemetics, when appropriate. Hematopoietic growth factors were allowed to treat grade 3 or 4 neutropenia or for neutropenic fever.
Dose modifications
If grade 3 treatment-related toxicity occurred, treatment was withheld until resolution of toxicity to grade ≤ 1 and restarted at the next lower dose. If grade 3 toxicity recurred or grade 4 toxicity occurred, treatment was discontinued.
| Table 1 Dose escalation schema of the protocol | ||||||
|---|---|---|---|---|---|---|
| Dose level | Lenalidomide PO (mg) daily × 21 days | Temsirolimus IV (mg) weekly × 28 days | Enrollment (N) | Completed cycle 1 (N) | DLT (N) | |
| 1 | 10 | 15 | 3 | 3 | 0 | |
| 2 | 10 | 20 | 6 | 6 | 0 | |
| 3 | 20 | 20 | 4 | 4 | 0 | |
| a The defined maximum tolerated | 4ª | 20 | 25 | 4 | 4 | 0 |
| dose | Expansion | 20 | 25 | 26 | 20 | 0 |
| PO orally; IV intravenous; DLT dose-limiting toxicity | Total | 43 | 37 | 0 | ||
Patient monitoring
Patients underwent a complete clinical evaluation every 4 weeks that included assessment for adverse events, a com- plete blood count, blood differential tests, and blood chemistry studies. All patients underwent radiological imaging for tumor staging after every two cycles of therapy (1 cycle=4 weeks).
Endpoints and statistical considerations
A conventional “3+3” study design was used. Toxicities were assessed using the National Cancer Institute Common Termi- nology Criteria for Adverse Events (NCI CTCAE), version 3.0 [13]. DLTs were assessed during the first cycle and defined as follows: any grade 3 or 4 non-hematologic toxicity, as defined in the NCI CTCAE, even if expected and believed to be unrelated to the study medications (including symptoms/ signs of vascular leakage or cytokine release syndrome but not including nausea and vomiting, electrolyte imbalances re- sponsive to appropriate regimens, or alopecia); any grade 4 hematologic toxicity (as defined by the NCI CTCAE) lasting 7 days or longer despite supportive care or associated with bleeding and/or sepsis; any grade 4 nausea or vomiting lasting more than 5 days despite maximum anti-nausea regimens; and any severe or life-threatening complica- tion or abnormality not covered in the NCI CTCAE. The MTD was defined by DLTs that occurred in the first cycle. Patients who had a response or stable dis- ease were allowed to remain on the study until progres- sion of disease, death, withdrawal of consent, or unac- ceptable toxicity occurred.
Best response was assessed by an MD Anderson Cancer Center radiologist every 2 cycles of therapy using the Re- sponse Evaluation Criteria in Solid Tumors (RECIST) guide- lines (version 1.0) [14]. These criteria define a partial response [6] as a 30 % or greater decrease in the sum of the longest diameters of target lesions, excluding complete disappearance of disease (complete response). Progressive disease was de- fined as a 20 % or greater increase in the sum of the longest diameters of target lesions. Stable disease (SD) was defined as changes not meeting the criteria for a PR or progressive
disease. Waterfall plot analysis was used to illustrate antitumor activity, if any, as previously described [15]. Responses shown in the waterfall plot (patients with clinical progression prior to radiological restaging were considered as having at least a 20 % increase) were grouped according to standard RECIST criteria.
Survival was measured from the start of treatment on protocol until death from any cause or last follow-up. Progression-free survival was measured from the start of treatment on protocol until progression or death, whichever occurred first. Overall survival was estimated from the start of treatment until death due to any cause. Statistical analyses were carried out using SPSS 19 computer software (SPSS, IBM Corporation, Armonk, NY).
Results
Patient characteristics
From September 2010 to January 2013, 43 patients were registered. Their median age was 58 years (range, 21-80). There were 26 men and 17 women. The most common diag- noses were colorectal cancer (N=5), sarcoma (N=5), neuro- endocrine carcinoma (N=4) and adenoid cystic carcinoma (N =4). Twenty-four (56 %) patients had two or more metastatic sites (range 1-7). The median number of prior therapies was three (range, 0-5). The median time from diagnosis to enroll- ment in the study was 29 months (range, 8-362). Baseline patient characteristics are shown in Table 2. Of 43 patients, 5 (11.6 %) had diabetes and 8 (18.6 %) had hypercholesterol- emia and/or hyperlipidemia at the time of enrollment. Tumor molecular profiling (EGFR, GNAQ, PIK3CA, PTEN, TP53, KIT, KRAS, NRAS, and BRAF) was performed in 33 (77 %) of the patients. Seventeen (52 %) of 33 patients had the following genetic aberrations: KRAS (N=5, 15 %), PIK3CA (N=3, 9 %), TP53 (N=2, 6 %), KRAS and PIK3CA (N=1, 3 %), KRAS, TP53, and PIK3CA (N=1, 3 %), EGFR (N=1, 3 %), NRAS (N=1, 3 %), PIK3CA and KIT (N=1, 3 %), TP53 and PTEN (N=1, 3 %), and PTEN mutation (N=1, 3 %).
| Characteristics | No. of patients (N=43) |
|---|---|
| Females (%) | 17 (40) |
| Age in years, median (range) | 58 (21-80) |
| Performance status >1 (%) | 1(2) |
| ≥2 metastatic sites (%) | 24 (56) |
| RMH score ≥2 (poor risk) (%) | 13 (30) |
| No. of prior Rx, median (range) | 3 (0-5) |
| Tumor type | |
| Colorectal carcinoma | 5 (12) |
| Soft tissue sarcoma | 5 (12) |
| Adenoid cystic carcinoma | 4 (9) |
| Neuroendocrine carcinoma | 4 (9) |
| Adrenocortical carcinoma | 3 (7) |
| Head and neck squamous cell carcinoma | 3 (7) |
| Non-small cell lung carcinoma | 2 (5) |
| Endometrial carcinoma | 2 (5) |
| Parotid adenocarcinoma | 2 (5) |
| Merkel cell carcinoma | 2 (5) |
| Otherª | 11 (26) |
a 1 patient each had appendiceal mucinous carcinoma, cutaneous basal cell carcinoma, urinary bladder transitional cell carcinoma, chondrosarcoma, ocular melanoma, non-seminomatous germ cell tumor, salivary gland acinic cell carcinoma, salivary gland mucoepidermoid carcinoma, thymic carcinoma, thymoma, and vulval squamous cell carcinoma RMH Royal Marsden Hospital score (Garrido-Laguna, 2012 #2898)
Dose escalation and dose-limiting toxicity
Overall, 121 cycles (median: 2/patient; range: 1-11) were administered. Of the 43 patients who started the study medi- cations, 37 completed at least one cycle of therapy. Six pa- tients did not complete the first cycle for the following rea- sons: three had progression of disease and worsening perfor- mance status and came off study and three withdrew consent. None of these six patients had significant toxicity from the study medications.
The dose escalation schema and the number of patients treated at each dose level are listed in Table 1. No DLT was observed during the dose-escalation portion of the study; therefore, the highest dose level tested (lenalidomide 20 mg on days 1-21 and temsirolimus 25 mg on days 1, 8, 15, and 22) was used in the expansion phase.
Toxicity
Of 43 patients who received treatment, 18 (42 %) patients had no toxicity greater than grade 1. The most common non- hematologic toxicities were hyperglycemia (74 %), fatigue (42 %), hypertriglyceridemia/hypercholesterolemia (40 %), skin rash (33 %), mucositis (19 %), and infections (12 %)
(Table 3). The grade 3/4 non-hematologic toxicities were: grade 3 hyperglycemia (N=9), grade 3 hypertriglyceridemia (N=3), and grade 4 infection (N=1), which occurred in cycle 5 and was successfully managed with IV antibiotics and fluid support. Grade 3/4 hematologic toxicity occurred in 18 pa- tients (neutropenia, 12; thrombocytopenia, 6). Twelve patients required treatment with granulocyte colony-stimulating factor (filgrastim) for management of neutropenia.
Dose reduction of lenalidomide was required in four pa- tients owing to hematologic toxicity, and dose reduction of temsirolimus was required in one patient owing to grade 2 mucositis. Two patients had dose reductions of both lenalidomide and temsirolimus because of grade 3 neutrope- nia (N=1) and both grade 3 thrombocytopenia and grade 2 skin rash (N=1).
No patients discontinued treatment because of toxicity. Thirty (70 %) patients received prophylactic anticoagulation therapy. No thromboembolic events were reported. There were no deaths due to toxicity.
Toxicity evaluation at the maximum tolerated dose
Thirty patients were treated at dose level 4 (Table 1). Overall, 89 cycles were administered at this dose level, with a median of two cycles per patient (range, 1-11). Six patients experienced
| Adverse event (%) | Grade | 1 Grade | 2 Grade 3 | Grade 4 | Total |
|---|---|---|---|---|---|
| Non-hematologic | |||||
| Hyperglycemia | 19 | 35 | 21 | 74 | |
| Fatigue | 28 | 14 | 42 | ||
| Hypercholesterolemia | 33 | 6.7 | 40 | ||
| Hypertriglyceridemia | 13 | 6.7 | 20 | 40 | |
| Rash | 23 | 9 | 33 | ||
| Mucositis | 14 | 5 | 19 | ||
| Infection | 9 | 2 | 12 | ||
| Anorexia | 7 | 2 | 9 | ||
| Diarrhea | 7 | 2 | 9 | ||
| Nausea/Vomiting | 7 | 7 | |||
| Renal failure | 5 | 2 | 7 | ||
| Neuropathy | 5 | 5 | |||
| Headache | 2 | 2 | |||
| Pneumonitis | 2 | 2 | |||
| Transaminitis | 2 | 2 | |||
| Weight loss | 2 | 2 | |||
| Hematologic | |||||
| Neutropenia | 2 | 9 | 28 | 40 | |
| Thromboxytopenia | 2 | 12 | 12 | 2 | 28 |
| Anemia | 7 | 5 | 12 |
grade 3/4 neutropenia, and three patients experienced grade 3/4 thrombocytopenia.
Response evaluation
Forty of the 43 patients were evaluable for response; three patients withdrew consent before response was assessed. Of these 40 patients, one had a PR and 19 (48 %) had SD (Table 4). The waterfall plot (tumor restaging by RECIST which was available in 39 patients) is shown in Fig. 1a. Overall, six (15 %) patients had SD for ≥ 6 months (including the patient who had a PR) (Table 5). All six patients were treated at the highest dose level. All had molecular profiling data available, but no mo- lecular aberrations were detected in their tumors.
The patient with a PR was a 71-year-old woman with neuroendocrine carcinoma who was diagnosed 11 months prior to protocol enrollment and whose disease had progressed rapidly on two prior lines of therapy, including platinum and gemcitabine (Fig. 1b). She remained on protocol with lenalidomide plus temsirolimus therapy for 8.2 months (8 cycles). She discontinued treatment because of disease progression.
The patients with SD ≥ 6 months had the following tumor types: soft tissue sarcoma (2 [40 %] of 5), adenoid cystic carcinoma (1 [25 %] of 4), parotid adenocarcinoma (1 [50 %] of 2), adrenocortical carcinoma (1 [33 %] of 3), and neuroen- docrine carcinoma (1 [25 %] of 4). No association was found between the patients’ tumor molecular profiles and clinical benefit. Two patients had SD lasting for >10 months. One was a 30-year-old man with soft tissue sarcoma diagnosed 4.6 years before trial enrollment who had undergone three prior therapies (doxorubicin and ifosfamide; gemcitabine and docetaxel; and single-agent trabectidin); he remained on lenalidomide plus temsirolimus therapy for 10.9 months and discontinued treatment because of progressive disease. The
other patient was a 60-year-old woman with adenoid cystic carcinoma diagnosed 1 year prior to enrollment who had progressed on cisplatin at the time of trial enrollment. As of March 2013, she remained in the study, without progression after 12 months of therapy. All these patients had evidence of progressively growing tumors prior to study enrollment and subsequent tumor shrinkage/stabilization as shown in Fig. 2.
At the time of last follow-up, five patients were continuing on protocol and 38 had stopped protocol therapy because of progressive disease (N=32), withdrawal of consent (N=5; 2 patients before completing cycle 1, 1 patient during cycle 2, 1 patient after cycle 3, and 1 patient after cycle 6), or loss to follow-up (N=1; after 3 cycles).
Progression-free and overall survival
The median progression-free survival duration was 2.2 months (95 % CI, 1.5-2.9) (Fig. 3). Twenty-eight of the 43 patients had died at the time of last follow-up, including two patients who died while they were being treated on protocol. All deaths were due to progressive disease. The median overall survival duration was 7.8 months (95 % CI, 5.1-10.6; range, 0.1 to 27.2 months) (Fig. 3).
Discussion
This is the first study to evaluate the combination of lenalidomide and temsirolimus in patients with advanced malignancies. We observed that this is a safe combination with evidence of clinical benefit in selected patients with advanced cancer. As there were no dose-limiting toxicities, the last dose level tested in the escalation phase (lenalidomide at 20 mg 21/28 days orally and temsirolimus at 25 mg weekly) was chosen as the dose for the expansion phase. All non-
| Table 4 Clinical outcomes by tumor type | Tumor type | N | Evaluable (N)ª | Stable disease, N (%)b | Stable disease ≥6 months, N (%) |
|---|---|---|---|---|---|
| a Three patients were not evaluable for response because | Colorectal carcinoma | 5 | 5 | 1 (20) | 0 |
| Soft tissue sarcoma | 5 | 5 | 3(60) | 2 (4) | |
| Adenoid cystic carcinoma | 4 | 4 | 4 (100) | 1 (25) | |
| they withdrew consent prior to | Neuroendocrine carcinoma | 4 | 4 | 4 (100)℃ | 1 (25) |
| response assessment | Adrenocortical carcinoma | 3 | 3 | 2 (67) | 1 (33) |
| b Best response | Head and neck squamous cell carcinoma | 3 | 3 | 0 | 0 |
| " One patient with neuroendocrine carcinoma had a partial response | Non-small cell lung carcinoma | 2 | 1 | 0 | 0 |
| d See Table 2 for list of other | Endometrial carcinoma | 2 | 1 | 0 | 0 |
| diagnoses | Parotid adenocarcinoma | 2 | 2 | 1 (50) | 1 (50) |
| e Other diagnoses with SD were 1 | Merkel cell carcinoma | 2 | 2 | 2 (100) | 0 |
| patient each with basal cell carci- | Other d | 11 | 10 | 3 (30)€ | 0 |
| noma, salivary gland acinic cell carcinoma, and thymoma | Total | 43 | 40 | 20 (50) | 6 (15) |
a
150
100
50
0
-50
-100
b
R
R
a
b
hematologic toxicities were grade 2 or lower and 18 (42 %) patients had no toxicity greater than grade 1. All grade 3/4 toxicities were reversible, and no patient discontinued the study drug therapy because of toxicity.
The most common non-hematologic adverse events (ob- served in ≥10 % of patients) were hyperglycemia, fatigue, hyperglyceridemia, hypercholesterolemia, skin rash, mucositis,
and infections. Hyperglycemia and hyperlipidemia have been reported as common adverse events after temsirolimus treat- ment, affecting 17-26 % and 6-27 % treated patients respec- tively [16, 17]. Skin rash occurs in 6 %-11 % of patients with solid tumors treated with lenalidomide [4, 18] and in 47 %- 75 % of patients treated with temsirolimus [16, 17, 19]. The combination of lenalidomide with temsirolimus in patients with
| Age/Sex | ECOG PS | Histologyª | Time from Diagnosis, mos. | Prior Rx,N | Disease Sites, N | LDH, IU/L | RECIST% | Cycles, | N PFS,mos. | Progression | Survival, mos | Survival status |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 63/M | 1 | Adenocarcinoma, parotid | 36 | 2 | 2 | 377 | -10 | 6 | 7.6 | Yes | 13.8+ | Alive |
| 30/M | 1 | Soft tissue sarcoma | 55 | 2 | 4 | 448 | -8 | 11 | 10.9 | Yes | 13.5 | Dead |
| 72/F | 1 | Adrenocortical carcinoma | 53 | 3 | 4 | 380 | -2 | 5 | 6 | No | 14.5+ | Alive |
| 60/F | 0 | Adenoid cystic carcinoma | 16 | 1 | 1 | 451 | 0 | 9+ | 12.4+ | No | 12.4+ | Alive |
| 62/M | 1 | Soft tissue sarcoma | 29 | 3 | 3 | 548 | -21 | 8 | 8.5 | Yes | 11.6+ | Alive |
| 71/F | 1 | Neuroendocrine carcinoma | 10 | 2 | 2 | 1040 | -51 | 8 | 8.2 | Yes | 13.1 | Dead |
ª No tumor molecular aberrations were found in these patients
Rx treatment; LDH lactate dehydrogenase, RECIST response evaluation criteria in solid tumors; PFS progression free survival; mos months; M male; F female
20
Tumor measurements as % of the baseline
10
0
-10
-20
-30
-40
-50
-60
-70
4 mo prior 2 mo prior baseline 1st restage 2nd restage 3rd restage 4th restage 5th restage 6th restage 7th restage
pt no. 1
pt no. 2
pt no. 3
pt no. 4
pt no. 5
pt no. 6
myeloma was associated with skin rash in 76 % of patients, although no skin rash was reported in another study involving patients with lymphomas [10, 20]. We observed skin rash in 32 % of treated patients, which is actually lower than the reported incidence with single-agent temsirolimus. Fatigue was noted in 41 % of our patients; this incidence was similar to that in previously published studies of single-agent temsirolimus (38 %-51 %) [16, 17, 19] but much lower than the 90 % incidence reported for temsirolimus used in combina- tion with lenalidomide in patients with myeloma [10]. Mucositis was observed in 18 % of the treated patients in our study, which is similar to the 20 % mucositis rate reported in a
100
MPFS
.JTOS
censored
censored
80
Survival %
60
40
20
0
0
6
12
18
24
30
Time (months)
phase 3 trial of single-agent temsirolimus in renal cell carcino- ma; thus, the mucositis we observed is possibly attributable entirely to the effect of temsirolimus [17].
The most common hematologic toxicity was reversible neu- tropenia, which occurred in 17 (40 %) patients. Grade 3/4 neutropenia is uncommon with temsirolimus (0-3 %), but lenalidomide can cause grade 3/4 neutropenia, although the reported incidence is variable (2.7 %-50 %) [21-24]. We observed a relatively high incidence of grade 3/4 neutropenia in our study (28 %), which may have been due to an additive effect of these agents, to the advanced nature of the cancers in these patients, or to the extensive prior therapies with cytotoxic agents. The same reasoning could explain the high rate of grade 3/4 thrombocytopenia (14 %) in the patients treated. In solid tumors, grade 3/4 thrombocytopenia is rare with single-agent lenalidomide (0-11 %) and temsirolimus (0-1 %) [16, 17, 21-24]. The hematologic adverse events were reversible in all patients, and they were not associated with infections, except in one patient who developed neutropenic sepsis during the fifth cycle of treatment; the patient recovered. Thromboembolism is a serious adverse event of lenalidomide and has been reported in up to 3 % of patients with solid tumors treated with 5-25 mg of lenalidomide [21, 22]. Three-fourth of our patients received prophylactic anticoagulation, and none developed thromboem- bolic complications.
Clinical benefit with this combination, as evidenced by prolonged stable disease (≥6 months) or partial response, was noted in two patients with soft tissue sarcoma and in one patient each with adenoid cystic carcinoma, parotid adenocar- cinoma, adrenocortical carcinoma, and neuroendocrine carci- noma. Synergism between these agents has been described in earlier studies in multiple myeloma and more recently in
lymphomas [10, 20]. Soft tissue sarcomas and neuroendocrine cancers may respond to mTOR inhibitors, as evidenced by recent phase II and III trial results [25-27]. Although single- agent lenalidomide has no antitumor activity in soft tissue sarcomas, an additive effect with temsirolimus is possible [18]. Parotid adenocarcinoma and adenoid cystic carcinoma are rare tumors with no standard therapy options, and the activity demonstrated by this combination needs to be evalu- ated further. All responses noted were at dose level 4, which suggests a dose-dependent effect. Unfortunately, the absence of pharmacokinetic data and the small number of patients treated preclude further interpretation.
Molecular abnormalities involving the PI3K/AKT/mTOR pathway may be associated with the clinical benefits of mTOR inhibitors such as temsirolimus [28]. Tumor molecular profil- ing was available for 33 of the patients studied and demon- strated PIK3CA mutations in six patients. However, no corre- lation was noted between the clinical benefit of therapy and molecular abnormalities.
This is the first study to demonstrate the safety of combin- ing lenalidomide and temsirolimus in patients with advanced solid tumors. Further evaluation may be warranted in select tumor types in which anti-tumor activity was demonstrated.
Acknowledgments and funding
Funding source This research is supported in part by Celgene (provid- ed free lenalidomide and a research grant to Dr. Tsimberidou).
Conflicts of interest declaration P. Ganesan: None. S. Piha-Paul: None. A. Naing: None. G.Falchook: Research funding from Celgene. J Wheler: None. F. Janku: Research support from Novartis, Roche, Trovagene, Transgenomic, Biocartis. S. Laday: None. M. Kies: None. A.M. Tsimberidou: Research funding from Celgene.
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